Pharmacology

Pharmacology MD2012
Week 1 Pharmacology ............................................................................................................................ 8

ACh Cholinergic Transmission ...................................................................................................... 8
ACh Receptors .............................................................................................................................. 8
Where drugs can affect cholinergic transmission........................................................................... 9
NA/Dopamine Noradrenergic Transmission .............................................................................. 11
Adrenoceptors .............................................................................................................................. 11
Where dugs affect noradrenergic transmission ........................................................................... 12
Week 2 Pharmacology of IHD and MI ................................................................................................ 15
Learning Objectives........................................................................................................................... 15
Angina ............................................................................................................................................... 15
Angina Pain ................................................................................................................................... 15
Types of Angina ............................................................................................................................. 15
Principal Therapeutic Goals in Angina .......................................................................................... 16
Pharmacotherapy.......................................................................................................................... 16
Managing Angina .............................................................................................................................. 16
Normal Endothelial Cell Function ................................................................................................. 16
Organic Nitrates ............................................................................................................................ 17
Ca2+ Channel Antagonists .............................................................................................................. 19
Beta-blockers ................................................................................................................................ 20
Treating Myocardial Infarctions ........................................................................................................ 21
Week 3 Antihypertensives and Drugs for Heart Failure .................................................................... 22
Physiology of BP regulation .............................................................................................................. 22
Drug Targets .................................................................................................................................. 22
.......................................................................................................................................................... 24
ACE Inhibitors.................................................................................................................................... 24
Examples ....................................................................................................................................... 24
Indications ..................................................................................................................................... 24
Mechanism of Action .................................................................................................................... 24
Adverse effects ............................................................................................................................. 24
Contraindications/precautions ..................................................................................................... 24
Interactions ................................................................................................................................... 25
ANG II receptor (AT1) Antagonists (AKA Sartans) ............................................................................. 25
Examples ....................................................................................................................................... 25
Indications ..................................................................................................................................... 25
Mechanisms of Action................................................................................................................... 25
Adverse effects ............................................................................................................................. 25
Contraindications .......................................................................................................................... 26
Interactions ................................................................................................................................... 26
Alpha-adrenoceptor Antagonists ...................................................................................................... 26
Examples ....................................................................................................................................... 26
Indications ..................................................................................................................................... 26
Side effects/precautions ............................................................................................................... 26
Beta-blockers (Beta 1 selective)........................................................................................................ 26
Examples ....................................................................................................................................... 26
Indications ..................................................................................................................................... 26
Adverse effects ............................................................................................................................. 26
Interactions ................................................................................................................................... 27
Mixed Alpha and Beta-adrenoceptor Antagonists ........................................................................... 27
Examples ....................................................................................................................................... 27
Indications ..................................................................................................................................... 27
Calcium Channel Blockers ................................................................................................................. 27
Examples ....................................................................................................................................... 27
Indications ..................................................................................................................................... 27
Adverse Effects.............................................................................................................................. 28
Interactions ................................................................................................................................... 28
Diuretics ............................................................................................................................................ 28
Loop Diuretics ............................................................................................................................... 29
Thiazide Diuretics .......................................................................................................................... 29
Potassium-sparing Diuretics ......................................................................................................... 29
Centrally-acting anti-HTs................................................................................................................... 30
Examples ....................................................................................................................................... 30
Indications ..................................................................................................................................... 30
Adverse effects ............................................................................................................................. 30
Interactions ................................................................................................................................... 31
Endothelin Receptor Antagonists ..................................................................................................... 31
Examples ....................................................................................................................................... 31
Indications ..................................................................................................................................... 31
Adverse effects ............................................................................................................................. 31
Contraindications/precautions ..................................................................................................... 31
Pathophysiology of HF ...................................................................................................................... 32
Approaches to drug treatment ..................................................................................................... 32
Aldosterone Antagonists................................................................................................................... 32
Examples ....................................................................................................................................... 32
Sympathomimetics (not used much any more)................................................................................ 33
Examples ....................................................................................................................................... 33
Indications ..................................................................................................................................... 33
Digoxin/Digitalis (Cardiac glycoside) see week 4 .............................................................................. 33
Indications ..................................................................................................................................... 33
Adverse Effects (see GLS apparently, is it a negative dromotropic drug??) ................................. 33
Interactions ................................................................................................................................... 33
Sinus Node Inhibitors ........................................................................................................................ 34
Examples ....................................................................................................................................... 34
Indications ..................................................................................................................................... 34
Neprilysin Inhibitors .......................................................................................................................... 34
Examples ....................................................................................................................................... 34
Indications ..................................................................................................................................... 34
Adverse effects ............................................................................................................................. 34
Drug treatment for HT ...................................................................................................................... 34
Drug Treatment of HF ....................................................................................................................... 36
Week 4 Therapeutic Management of Dysrhythmias and Atherosclerosis ........................................ 38
Dysrhythmias and their treatment ................................................................................................... 38
What is Dysrhythmia? ................................................................................................................... 38
Underlying Mechanisms ............................................................................................................... 39
Phases of Cardiac Action potential ............................................................................................... 41
Major Classes of Anti-dysrhythmic Drugs ..................................................................................... 42
Summary ....................................................................................................................................... 48
Atherosclerosis and its treatment .................................................................................................... 49
Major Drug Classes to treat Dyslipidemia..................................................................................... 49
Week 5 Drugs for Homeostasis .......................................................................................................... 54
Hemostasis ........................................................................................................................................ 54
Virchows Triad ............................................................................................................................. 54
Antithrombotic agents .................................................................................................................. 55
Anticoagulants .................................................................................................................................. 55
Heparin.......................................................................................................................................... 55
Warfarin ........................................................................................................................................ 56
Thrombin Inhibitors ...................................................................................................................... 58
Antiplatelet Drugs ............................................................................................................................. 58
Aspirin ........................................................................................................................................... 58
Adenosine (same as last weeks adenosine) .................................................................................. 59
Glycoprotein IIb/IIIa receptor antagonists.................................................................................... 61
Fibrinolytic Drugs .............................................................................................................................. 62
Fibrin formation and breakdown .................................................................................................. 62
Streptokinase ................................................................................................................................ 62
Tissue Plasminogen Activators...................................................................................................... 62
Week 6 Endocrine and Reproductive Pharmacology......................................................................... 64
Thyroid Disorders and Pharmacology ............................................................................................... 64
General therapeutic approach to hormone disturbances ............................................................ 64
Hyperthyroidism and pharmacotherapy ...................................................................................... 64
Hypothyroidism and pharmacotherapy ........................................................................................ 65
Glucocorticoid Pharmacology ........................................................................................................... 66
Glucocorticoids ............................................................................................................................. 66
Reproductive Pharmacology ............................................................................................................. 67
Oral Contraception........................................................................................................................ 67
Menopause ................................................................................................................................... 69
Men ............................................................................................................................................... 71
Oxytocin ........................................................................................................................................ 72
Week 7 Diabetes and Obesity Pharmacology .................................................................................... 73
Diabetes Pharmacology .................................................................................................................... 73
Patho/physiology .......................................................................................................................... 73
Treatment of Diabetes ...................................................................................................................... 76
Insulin ............................................................................................................................................ 76
Incretin-mimetic Drugs ................................................................................................................. 77
Biguanides (e.g. Metformin) ......................................................................................................... 77
Sulfonylurea Drugs (e.g. Tolbutamide, Glibenclamide, Glipizide) ................................................ 78
Thiazolidinediones (e.g. Pioglitazone) .......................................................................................... 78
Gliptins (e.g. Sitagliptin, vildagliptin) ............................................................................................ 78
Alpha-glucosidase inhibitors (Acarbose)....................................................................................... 78
Summary table .............................................................................................................................. 79
SGLT2-inhibitors (e.g. Dapagliflozin, Canagliflozin) ...................................................................... 79
Obesity Pharmacology ...................................................................................................................... 80
Obesity .......................................................................................................................................... 80
Discontinued Pharmacotherapy ................................................................................................... 81
Pharmacological management of obesity .................................................................................... 81
Summary Tables ............................................................................................................................ 84
Week 8 GI Pharmacology ................................................................................................................... 85
GI Pharmacology ............................................................................................................................... 85
Pro-kinetic Agents ......................................................................................................................... 85
Antimotility and Antispasmodic Agents........................................................................................ 86
Nausea, Vomiting and Anti-emetics ............................................................................................. 86
GORD Gastro-oesophageal reflux disease ................................................................................. 88
Pancreatitis ................................................................................................................................... 91
Milk-alkali Syndrome .................................................................................................................... 91
Week 10 Pharmacology of Pain and Analgesia .................................................................................. 93
Pharmacology of Pain ....................................................................................................................... 93
Pain................................................................................................................................................ 93
Pharmacological Management of acute pain ............................................................................... 94
Peripherally-acting Analgesics ...................................................................................................... 94
Centrally-acting Analgesics ........................................................................................................... 95
Adjuvants ...................................................................................................................................... 98
Chronic Pain Neuropathic Pain ................................................................................................ 100
Week 11 Pharmacology of Psychotic Disorders ............................................................................... 103
Learning Objectives......................................................................................................................... 103
Schizophrenia .................................................................................................................................. 103
Symptoms ................................................................................................................................... 103
Aetiology ..................................................................................................................................... 104
Dopaminergic Pathways/Systems in Brain ................................................................................. 104
Dopamines Role in Schizophrenia.............................................................................................. 105
Pharmacotherapy........................................................................................................................ 106
Bipolar Disorder .............................................................................................................................. 107
Pharmacology Mood stabilizers and others............................................................................. 107
Week 12 Pharmacology of Neurodegenerative Diseases, Epilepsy and Drug Addiction................. 111
Learning Objectives......................................................................................................................... 111
Parkinsons disease ......................................................................................................................... 111
Parkinsons .................................................................................................................................. 111
Symptoms ................................................................................................................................... 111
Physiology of Dopaminergic Systems in Brain ............................................................................ 112
Pathophysiology of Parkinsons .................................................................................................. 113
Pharmacological Treatment of PD .............................................................................................. 114
Alzheimers Disease ........................................................................................................................ 116
Alzheimers Disease .................................................................................................................... 116
Pathogenesis ............................................................................................................................... 116
Pharmacological Treatment ........................................................................................................ 116
Epilepsy ........................................................................................................................................... 117
Epilepsy ....................................................................................................................................... 117
Pharmacological Treatment ........................................................................................................ 117
Side-effects of Antiepileptics ...................................................................................................... 119
Drug Addiction ................................................................................................................................ 119
Drug Addiction ............................................................................................................................ 119
Brain Circuits Involved ................................................................................................................ 119
Genetic and Environmental Effects ............................................................................................ 120
Treatments .................................................................................................................................. 120
Week 1 Pharmacology
Learning Objectives
ACh neurotransmission
o Synthesis, storage, release, breakdown, receptors
o Drugs which affect cholinergic transmission
Drugs which act at autonomic ganglia/neuromuscular junction
NA neurotransmission
o Synthesis, storage, release, breakdown, reuptake, receptors
o Drugs which affect noradrenergic transmission
Peripheral/Autonomic NS Pharmacology
ACh Cholinergic Transmission
ACh produced by neurons by acetylation of choline and acetyl-coA

o Enzyme Choline acetyltransferase
Found only in cholinergic neurons
ACh stored in vesicles via Vesicular Acetyl Choline Transporter (VAChT)
Broken down by (inactivated by) cholinesterase enzymes
o Broken down choline (taken back up into neuron after breakdown) and acetate
ACh Receptors
Nicotinic receptors nAChR

o Ligand gated (ionotropic receptors)
o Mediate fast excitatory transmission (EPSPs) at Neuromuscular junction and
autonomic ganglia (both PNS and SNS)
o Also occur in some areas of CNS
Muscarinic receptors (mAChR)
o G protein coupled
Hence produce either slow excitatory or inhibitory synaptic responses
(EPSPs or IPSPs) on neurons (contraction/relaxation on a tissue target)
o 5 subtypes
M1-5
M1,3,5 Excite/Stimulate (odds)
IP3 2nd messenger system
M2,4 Inhibit (evens)
cAMP 2nd messenger system
M1 Neural (Autonomic ganglia)
M2 Heart (atria)
M3 Smooth muscle and glands
o Present at postganglionic parasympathetic targets
o Also found in CNS
Where drugs can affect cholinergic transmission
Mimic action of ACh at mAChR or mAChR (agonists)

o mAChR agonists (parasympathomimetics)
Mimic effects of PNS leading to bradycardia, smooth muscle contraction
(bronchioles)
Few receptor selective agonists due to structural similarity of mAChR
Hence few clinical uses (nonselective actions)
o nAChR agonists
Mimic stimulation of both SNS and PNS via nAChR on autonomic ganglia
Stimulate CNS nAChR
Rarely used clinically
Block action of ACh at receptors (antagonists)
o mAChR antagonists
Blocks the effects of PNS leading to tachycardia, inhibition of secretions
and smooth muscle relaxation (bronchioles) etc.
Muscarinic receptors are structurally similar, hence hard to specialise for a
single receptor subtype (e.g. M3)
o nAChR antagonists
Produced widespread effects and are not used clinically
Inhibit synthesis/release of ACh
o Inhibition of synthesis of ACh by blocking choline reuptake
o Inhibit vesicular storage of ACh
o Inhibit release of ACh
E.g. Botox (Botulinum toxin)
Cleaves SNAP-25 protein hence preventing exocytosis of ACh
vesicles
Inhibit breakdown of ACh
Enhance cholinergic transmission
o Anticholinesterases (cholinesterase inhibitors)
Stop ACh breakdown hence greatly increases ACh at synapse
Clinically
Used to reverse non-depolarising blockers
Alzheimers disease, Myasthenia Gravis
Drugs acting at the Neuromuscular junction
o Used during surgery to relax muscle so contraction doesnt occur during operation
o Non-depolarising blockers
Competitive muscle type nAChR antagonists
Binds to nicotinic receptors at diaphragm and skeletal muscles
o Depolarising blockers
Super agonists which activate nicotinic receptors (which need to be reset)
to produce sustained depolarisation
Nicotinic receptors are activated then inactivated but then not reset as the
super agonist is not broken down by enzymes
NA/Dopamine Noradrenergic Transmission
Two main receptor classes alpha and beta

o Alpha 1, 2
o Beta 1, 2, 3
o All g protein coupled
Synthesis of catecholamines from Tyrosine
o Tyrosine - DOPA - Dopamine Noradrenaline Adrenaline
NA and dopamine are stored in synaptic vesicles via VMAT2
NA action is terminated by
o Reuptake mainly into the nerve terminals via Norepinephrine Transporter (NET)
o Enzymatic breakdown Monoamine Oxidase (MAO) and Catechol-O-methyl
transferase (COMT)
Adrenoceptors
Alpha 1
o Vasoconstriction
o Bronchoconstriction
o Relax gut smooth muscle
Alpha 2
o Vasoconstriction
o Inhibition of insulin release
o Present on ACh and NA releasing neurons to prevent release of these
neurotransmitters (presynaptic)
Beta 1
o Increase HR and contractility (force of contraction of heart)
Beta 2
o Vasodilation
o Bronchodilation
o Relax gut and urinary smooth muscle
Beta 3
o Promote thermogenesis
and lipolysis
Where dugs affect noradrenergic transmission
Activation or blockage of receptors

o Agonists
Direct acting sympathomimetics
Asthma Beta 2 agonists dilate bronchioles
o Antagonists
Severe Hypertension Alpha 1 selective antagonists
Synthesis of NA
Storage of NA
Release of NA
o Amphetamine
Are taken up into nerve terminals (via NET) and vesicles (via
VMAT) thus displacing NA which can then activate receptors
Uptake of NA
Breakdown of NA
o MAO (intracellular) inhibitors
Also increase dopamine and serotonin as well as NA
Week 2 Pharmacology of IHD and MI
Learning Objectives
1. Blood supply and oxygen demand of heart and how changes in this can lead to angina and
MI
2. Main mechanisms of action of drugs used in treatment of IHD
3. Different types of angina and how they can be targeted pharmacologically
4. Potential drug interactions and mechanisms of action
5. Side effects and potential toxicity of drugs used in treatment of IHD
Angina
AKA Angina Pectoris is a symptom
It is the primary symptom of ischaemic heart disease
o IHD Either due to atherosclerosis or sudden constriction of the blood vessel or
something physically blocking the blood vessel, the heart is not getting enough
blood, thus not enough oxygen or glucose
Angina Pain
Due to insufficient blood perfusion, cardiac muscle uses anaerobic respiration

o Hence, build-up of lactic acid
o Failure to remove waste products
Nociceptive receptors (acid-sensing primary sensory neurons) are activates by build-up of
o Lactic acid
o H+
o ATP etc.
Types of Angina
Stable (angina due to increase in demand)

o Predictable
o Due to atherosclerosis of the coronary blood vessels
Hence, decreased coronary blood flow always
o When there is an increase in oxygen demand (activation of the sympathetic NS), the
supply is still the same (as it is a stable plaque), thus angina develops
Unstable (angina due to block in supply)
o Unpredictable
o Due to an abrupt decrease in blood flow (coronary thrombosis)
In this case, angina develops because the issue is supply decrease, not
demand increase
o Does not require an increased demand (due to activation of sympathetic NS for
example), it can just happen
Prinzmetal (variant)
o Angina develops due to localised vasospasm (functional constriction)
Principal Therapeutic Goals in Angina
Stable
o Reduce myocardial oxygen demand
Via decreasing HR, myocardial contractility, and/or ventricular wall stress
Unstable
o Increase myocardial blood flow
Antiplatelet agents
o Reduce intracoronary thrombosis
Heparin
o Restore flow by mechanical means
Coronary stents
Emergency coronary bypass surgery
Prinzmetal
o Prevent coronary vasospasm
Pharmacotherapy
Anti-thrombotics and drugs which decrease atherosclerosis (statins) are for longer term use,
not acutely
Managing Angina
Three primary drug classes
o Organic Nitrates
o Calcium channel blockers
o Beta blockers
Normal Endothelial Cell Function
Endothelial cells themselves cannot contract/relax, however, neighbouring smooth muscle

cells (in tunica media) can and endothelial cells can help them to contract/relax
They do this through the release of chemicals in response to other chemicals release
o Adenosine (vasodilator)
Stimuli ACh, 5-HT, Thrombin, Shear stress
o Prostacyclin (vasodilator)
o Endothelin 1 (vasoconstrictor)
Stimuli Thrombin, Angiotensin II, Adrenaline
o Nitric Oxide (NO) (vasodilator)
These stimuli increase NO production and release from endothelial cell
1. Then NO acts on smooth muscle cells by activating cGMP system
2. This leads to dephosphorylation of myosin light chain kinase
o MLCK phosphorylates the myosin light chain, thus
allowing cross bridge formation and contraction
o Hence blocking MLCK will prevent contraction
3. Vasodilation
Organic Nitrates
Exogenous sources of NO
o Glyceryl trinitrate (GTN), isosorbide mononitrate, isosorbide dinitrate
Mechanism of Action
o Metabolically liberated (because it is usually administered as a prodrug) NO
activates guanylyl cyclase in vascular smooth muscle
o This synthesises cGMP, hence levels within the cell increase
o Elevated cGMP closes vascular smooth muscle calcium channels and
dephosphorylation of MLC (hence cross bridges cant form)
o Hence vasodilation of veins, muscular arteries, aorta
Immediate and potent vasodilation
o Decreases venous return, hence preload, hence oxygen demand
o Decreases afterload (due to small vasodilation of elastic arteries closest to heart
(aorta)), hence decrease oxygen demand
o However, these effects depend largely on dose and type of nitrate administered
Low Dose Organic Nitrates
o Preferentially dilate veins over arterioles
Hence, decrease venous return, decrease preload
Slight decrease in systemic arterial pressure
Slight decrease in pulmonary vascular resistance
Slight decrease in cardiac output
High Dose Organic Nitrates
o Further venous pooling (dilation of veins)
o Decrease in arteriolar resistance
Hence, decrease afterload
Decrease in systolic and diastolic BP and cardiac output
Leading to weakness, dizziness, pallor
This can reduce coronary flow
o Hence, decreased supply
Compensatory activation of sympathetic NS (via baroreceptors) due to
decrease in BP
Hence, reflex tachycardia
Adrenergic enhancement of contractility
o Coronary Vasodilation
May increase transiently, but may decrease later if cardiac output and BP fall
Overdosing on Organic Nitrates may cause the Bezold-Jarisch reflex:
o There is a lot of venous pooling (because of the organic nitrates)
o Hence, the sympathetic NS is activated as compensation for the decrease in BP etc.
o Thus contractility and HR increase, but little blood in ventricles (because of venous
pooling)
Thus, vigorous contraction of poorly filled ventricle
o This activates sensory C fibres going to brainstem (IDK WHY??)
It may be due to the increase pressure inside the LV due to increase
contractility and heart rate, thus decrease sympathetic tone to compensate
for the increased pressure
o The brain understands this as a sympathetic over activation and increases PNS
activation whilst also decreasing SNS activation
Thus bradycardia WITH hypotension (no compensation due to no SNS
activation)
To combat, administer Atropine (a mAChR antagonist, hence
Parasympatholytic)
Tolerance may develop
o Thus patients must have drug-free periods
o Patients with no tolerance can develop the Bezold-Jarisch reflex
Clinical applications
o Acutely
Managing acute angina attack
Administered sublingually
o Chronically
As a prophylactic measure by chronically decreasing Oxygen demand of
heart
Administered as slow release tablets or patches
Interactions with PDE5 inhibitors
o Men with CAD may have erectile dysfunction
o PDE5 is an enzyme which breaks down cGMP (phosphodiesterases breakdown both,
cGMP and cAMP)
o PDE5 inhibitors are used in the treatment of erectile dysfunction
o Hence, if organic nitrates are used in presence of a PDE5 inhibitor (such as VIAGRA)
then there will be a profound increase in cGMP and thus there will be a dramatic
reduction in BP
Other effects of organic nitrates
o If something acts on vascular smooth muscle, it is likely to act on other smooth
muscles:
Bronchial smooth muscle relax (bronchodilation)
Biliary tract smooth muscle relax
GI tract smooth muscle relax and spontaneous motility decreased
Ca 2+ Channel Antagonists
Voltage gated Ca2+ channels (Long-type or Transient-type) mediate entry of extracellular Ca2+
into smooth muscles cells, cardiac myocytes and SA and AV nodal cells in response to an
electrical depolarisation
o This Ca2+ then inactivates calmodulin to form a Ca2+ calmodulin complex which
initiates contraction
o L-type Ca2+ channels in cardiac muscle
Hence, Ca2+ channel antagonists
o Relax vascular smooth muscle, especially in arterial beds (peripheral)
o Exert negative ionotropic and chronotropic effects
Reduced contractility and HR (respectively)
Hence, decrease in demand of heart
3 types of Ca2+ channel blockers
o Vascular selective
Nifedipine, nimodipine, amlodipine
More vascular dilation all over body, less cardiac effect
o Cardioselective
Verapramil
More active on heart than on systemic vasculature
o Non-selective
Diltiazem
Mechanism of Action
o Block Ca2+ channels to decrease Ca2+ availability intracellularly at SA and AV nodes
and ventricular muscle (Cardioselective) or in vascular smooth muscle (vascular
selective)
Negative chronotropy due to decrease Ca2+ in SA nodal cells
Negative ionotropy due to decrease availability of Ca2+ in ventricular cardiac
muscle cells
Hence, decrease demand (negative iono/chronotropy) and increase supply
(vasodilation/decrease vasoconstriction)
Clinically
o Considered second-line drugs
Except in Prinzmetal angina (angina due to vasospasm) where Ca2+ channel
blockers are primary choice
o Should not be used with beta-blockers in patients with history of arrhythmias
o Stable Angina (due to increased demand)
Increase blood flow (increase supply) via coronary artery dilation
Decrease myocardial oxygen demand (decrease demand) due to negative
iono/chronotropic effects
o Unstable Angina (due to decreased supply)
In some individuals, there is also a little bit of vasospasm as well as
thrombus block
In these individuals Ca2+ channel antagonists help
Classically, Ca2+ channel antagonists would not help
o Variant (Prinzmetal) Angina (due to vasospasm)
Increase blood flow (increased supply) due to local coronary vasodilation
Beta-blockers
Examples
o Propanolol, Sotalol, Esmolol, Atenolol,
Pindolol
Beta1-adrenergic receptor antagonists
o Act to decrease HR and contractility
Hence, decrease oxygen demand
Especially effective in Stable Angina as it directly
reduces oxygen demand, hence reducing the
stress-induced angina
Mechanism of Action
o Acts at SA and AV nodes and ventricular
muscle
o Decreases influx of Ca2+
o Decrease HR and contractility (decreases
demand)
Concerns
o Beta-blockers arent entirely Beta1 selective as Beta2 receptors may also be blocked
Beta2 receptors are found on bronchial smooth muscles
o Hence, Beta-blockers are contraindicated in patients with respiratory disorders as
they may cause bronchoconstriction
o Should not be used with Calcium channel blockers in patients with a history of
arrhythmias as they can cause fatal bradycardia
o SHOULD NOT be used in patients with variant angina as the increase in circulating
(or lack of decreases due to beta blockers) adrenaline stimulates vasoconstriction via
alpha adrenoceptors
They increase ejection time and end-diastolic volume due to decreased contractility (hence
decreased ejection time) and thus end-diastolic volume will be increased (because
decreased contractility, hence decrease in ejection volume), thus over-time will raise oxygen
demand of heart
o If used with organic nitrates they can reduce this effect due to their effect of
increased venous capacitance, hence decreased end-diastolic volume , thus less
blood left in ventricles after systole
Treating Myocardial Infarctions

Bed rest
Aspirin
Oxygen therapy
Beta-blockers
o Improve life expectancy after acute MI
Organic Nitrates
Morphine
o Allows for pain relief, hence decrease in stress hormones, hence reduced
sympathetic activation, hence decreased demand
o However, can mask ongoing ischemic symptoms
Anticoagulants
ACE inhibitors
Dont really want to be using Calcium channel blockers in an acute MI (especially one effecting the
LV) as the decreased contractility may compromise heart function
cAMP in cardiomyocytes causes contraction (opens Calcium channels, hence contraction)
cAMP in smooth muscle causes relaxation (activates PKA which inhibits MLCK, hence no cross-
bridge, no contraction)
Week 3 Antihypertensives and Drugs for
Heart Failure
Learning Objectives
Potential receptor, enzyme and ion channel targets for drugs to interact with cardiovascular
function
Pathophysiological mechanisms and processes responsible for the development of HT and
heart failure
Cellular mechanism of action of beta-blockers, alpha-blockers, calcium channel blockers, ACE
inhibitors, angiotensin II receptor antagonists, aldosterone antagonists, loop diuretics,
thiazide diuretics, potassium-sparring diuretics, sympathomimetics, digoxin, centrally-acting
antihypertensives, endothelin receptor antagonists, sinus node inhibitors and neprilysin
inhibitors
Explain the rationale for the therapeutic use for each of these drug classes in the treatment
of hypertension and/or heart failure
Explain the major adverse effects and important interactions and contraindications
associated with these drug classes
Outline the main current therapeutic approaches to pharmacotherapy of hypertension and
HF
Physiology of BP regulation
BP = CO x PVR
M2 receptors at SA node (innervated by PSNS)
Beta 1 receptors at SA node and Ventricles (innervated by SNS)
Alpha 1 receptors at blood vessels (innervated by SNS)
Beta 1 receptors at Kidneys to release renin (innervated by SNS)
o Angiotensin II stimulates Aldosterone release
Aldosterone increases Na reabsorption (and hence water)
o Angiotensin II also causes vasoconstriction
o Angiotensin II stimulates ADH release
ADH increases water reabsorption
Drug Targets
Hard to target M2 receptors as there are no good selective ones available so end up
stimulating whole PSNS system
Beta receptors can be targeted
o At heart decrease HR and contractility
o At kidney decrease renin production
Alpha receptors can be targeted
o At blood vessels causing vasodilation
o In the brain at presynaptic inhibitory alpha 2 receptors
ACE can be targeted
o Decrease in angiotensin II
Angiotensin II receptors can be targeted
Aldosterone receptors can be targeted
ADH receptors can be targeted
Calcium Channels can be targeted
Ion channels in the nephron could be targeted
Diuretics
Renin-Angiotensin-Aldosterone System could be targeted
Decreasing blood volume
Decreasing PVR
Inhibiting SNS
ACE Inhibitors
Examples
Names all end in pril

E.g. Perindopril
Indications
First line in HT and HF
Mechanism of Action
Inhibit ACE (angiotensin converting enzyme) from converting ANG I to ANG II, thus inhibiting
effects of ANG II:
o Inhibiting vasoconstriction hence decrease PVR
o Inhibiting Aldosterone release hence decrease blood volume
Aldosterone Na and H20 retention
o Inhibiting ADH release hence decrease blood volume
ADH H20 retention
ANG II also causes remodeling of cardiovascular tissue in the long term
Adverse effects
Dry cough (due to bradykinin build up), hypotension, hyperkalemia (due to aldosterones K+
excretion effect)
Contraindications/precautions
Angioedema (thought to be caused by similar mechanism as dry cough effect, local pain
mediators etc.)
Renal impairment increases risk of hyperkalemia
Interactions
Sartans work via the same MoA, hence should not be used with ACE-I
NSAIDs (non-steroidal anti-inflammatory drugs) may reduce anti-HT effect, increased risk
of renal impairment and hyperkalemia
o NSAIDs potentially (according to theory) can decrease the effects of any BP lowering
drugs except Calcium channel blockers
ANG II receptor (AT1) Antagonists (AKA Sartans)

Examples
All end in sartan

E.g. Irbesartan
Indications
HF and HT
Mechanisms of Action
Inhibit binding of ANG II to AT1 receptors (AT1 receptor antagonists)

AT1 ANG II receptor type 1 (GPCR)
Adverse effects
Hypotension, hyperkalemia
BUT NO COUGH
o Because no increase in Bradykinin levels (as ACE can still break it down)
Contraindications
Same as ACE-I
Interactions
Same as ACE-I
Alpha-adrenoceptor Antagonists
Examples
End in osin
E.g. Prazosin
Indications
HT
Decrease PVR via vasodilation mediated through alpha1-antagonism
Side effects/precautions
Postural Hypotension
Headache and drowsiness due to alpha1 receptors role in wakefulness
First dose hypotension when used with other anti-HTs
Beta-blockers (Beta 1 selective)

Examples
End in lol
E.g. Atenolol
Indications
Angina, HT, some helpful in HF, arrhythmias, post-MI

Commonly used, but not first line for HT
Inhibit sympathetic activity at Beta 1 receptors in heart

Reduce HR, contractility, CO and hence BP
Also act centrally to decrease sympathetic outflow (brainstem)
Also act at Beta 1 receptors at kidney to inhibit sympathetic stimulation of renin release
hence inhibit downstream effects of renin (ANG II, Aldosterone, ADH etc.)
Adverse effects
Hypotension, fatigue, bronchoconstriction (see wk 2 pharm notes), cold fingers/toes (due to

decreased blood vessel supply to skeletal muscle)
Decreased HR response to exercise
o Dampened sympathetic response to exercise
Postural Hypotension
Contraindications
Poorly controlled asthma

o Due to beta 2 antagonism in bronchiole smooth muscle
Bradycardia
Mask clinical signs of diabetes and hyperthyroidism
o Symptoms include tachycardia
Interactions
Other drugs that lower HR, BP

Other drugs that interact with adrenoceptors
NSAIDs (see above)
Mixed Alpha and Beta-adrenoceptor Antagonists

Examples
Really only one in use Carvedilol

o Used more with HF
Indications
Hypertension, HF, angina
Blocks both, Beta-1, 2 and Alpha-1 adrenoceptors

o Hence, reduces reflexes associated with decreased BP
o I.e. no reflex tachycardia due to decreased BP (via alpha antagonists) because of
beta-blockers
Net result would be slight decrease in HR
Reduces PVR via vasodilation via Alpha-1 antagonism
Calcium Channel Blockers

Examples
Two types
o Dihydropyridines Vascular selective (e.g. amlodipine)
All end in dipine
Can cause reflex tachycardia due to vasodilation
Not too much effect on heart
o Non-dihydropyridines e.g. Verapamil, Diltiazem
Can have vasodilator effects and cardiac effects
Useful for arrhythmias
Indications
HT, angina
Inhibit influx of Calcium via L-type (long) VGCCs

Effects depend on subclass of CCB and location of calcium channels inhibited
o Dihydropyridines Vasodilators with little cardiac effects
o Non-dihydropyridines Inhibit AV node conduction and reduce contractility (hence,
have negative dromotropic and ionotropic effects respectively)
Adverse Effects
Palpitations
Headache, flushing
o Due to low BP in arterial beds in face
Contraindications
Systolic HF, hypotension

Severe angina (dihydropyridines)
o Due to reflex tachycardia causing increase in oxygen demand
Interactions
Other drugs that lower BP, HR

Non-dihydropyridines can inhibit CYP3A4/5 (Cytochrome enzymes)
o Hence, drugs that are normally metabolized by these enzymes (which includes non-
dihydropyridines) will have their blood levels altered
Diuretics
Indications
o HT, oedema, HF
o Act on kidney to increase uresis
o Increased excretion of Na and water
Hence, reduced blood volume, hence reduced BP
Reduced pre-load, hence oxygen demand on heart
Main adverse effect is Hypokalemia
o Most channel systems the diuretics work on not only lead to Na excretion, but also K
excretion
Loop Diuretics
Examples
o Furosemide
Mechanism of Action
o Inhibit basolateral Na-K-2Cl pumps in the ascending limb of the Loop of Henle
Ascending limb is major site of reabsorption of Na (hence, highly potent)
Also causes increased K excretion
o Water follows, via osmosis, increasing diuresis, hence lowering blood volume
Main diuretic used in HF
Thiazide Diuretics
Examples
o Hydrochlorothiazide, indapamide
Doesnt necessarily have a thiazide group
Mechanism of Action
o Inhibits the Na-Cl co-transporter in the DCT
Decreased reabsorption
Hence, via osmosis, water excretion (follows Na ion)
Thus, decreased blood volume, thus decreased BP
Not as potent as Loop Diuretics
Main diuretic used in HT
May cause hypokalemia
Potassium-sparing Diuretics
Examples
o Amiloride
Mechanism of Action
o Blocks epithelial Na channels (ENaCs) on the apical membrane of the collecting
ducts
Hence, increased Na excretion, thus increased water excretion (via osmosis),
hence decreased blood volume and BP
No loss in K
o Fairly weak/limited effect
Thus, used with other diuretics to reduce K loss
Centrally-acting anti-HTs
Examples
Clonidine, methyldopa, moxonidine
Indications
HT
Work in brainstem to decrease sympathetic outflow

o Hence, inhibit effects of SNS
Clonidine and Methyldopa
o Agonists at CNS Alpha-2 adrenoceptors (type of autoreceptor)
Hence stimulates presynaptic mediated down-regulation of NE/NA release
into the synaptic cleft
Decreases sympathetic outflow, lowering BP via reduction of SNS effect on
HR, contractility and PVR
o Also evidence that they work at imidazoline receptors
Moxonidine
o Selective imidazoline receptor agonist
Results in reduced sympathetic outflow from CNS, hence decreased BP
Adverse effects
Dizziness, sedation, depression, erectile dysfunction, dry mouth, hypotension

Due to the host of side effects (mainly because it is a CNS acting drug) they are not used
front line
o Sometimes used first line in pregnancy (HT during pregnancy)
Contraindications
Bradycardia, Coronary artery disease (CAD), depression, diabetes, HF
Interactions
Other CNS depressants

Beta-blockers enhanced Bradycardia and hypotension
Endothelin Receptor Antagonists

Examples
Bosentan
Indications
Pulmonary arterial HT only
Endothelin-1 (ET-1) receptor antagonists

o Endothelin is a vasoconstrictor (released by endothelial cells) and increased BP,
hence, inhibition lowers BP
Adverse effects
Reduced hemoglobin, flushing, oedema, headache
Contraindications/precautions
Hepatic impairment
Pregnancy
Pathophysiology of HF
HF Inability of heart to produce enough
CO to meet metabolic demands of body
Systolic failure
o Inability of heart muscle to contract
(systole)
Impaired contractility +
increased afterload
Diastolic failure
o Inability of heart muscle to relax
Impaired diastolic filling
Most drugs talked about are used to treat
systolic HF
Approaches to drug treatment
Aim to improve CO, minimize congestion

and decrease cardiac workload/demand
o Decrease preload to reduce
congestion and cardiac workload
Diuretics
o Reduce afterload
Vasodilators
o Improve contractility
Positive ionotropic drugs
o Inhibit effects of RAAS activation
(compensatory)
ACE-I, AT1 antagonists,
Aldosterone antagonists
o Inhibit effects of SNS activation
(compensatory)
Beta blockers
Aldosterone Antagonists
Examples
Spironolactone
Mechanism of Action
Inhibits aldosterones DCT action (reabsorption of Na, secretion of K)

o Thus increased water secretion (following Na), thus decreased blood volume,
venous return and hence, preload
Inhibits aldosterones effects on heart (high levels stimulates hypertrophy and fibrosis of
cardiac muscle)
o Aldosterone antagonists thus provide cardioprotective effects
Dont seem to be as effective as other drugs in HT, hence not really used, but very useful for
HF
Sympathomimetics (not used much any more)

Examples
Adrenaline, dobutamine
Indications
HF secondary to MI, cardiac stress testing

o Short term use (after heart attack), NOT long term
Mimic actions of SNS

Variety of CV effects depending on receptor selectivity and activation compensatory reflexes
Stimulate beta-1 receptors on heart to increase HR and contractility
Digoxin/Digitalis (Cardiac glycoside) see week 4

Indications
Heart failure second line to ACE inhibitors

Some arrhythmias
Mechanism of Action
Normally, there is a Ca-Na antiporter in cardiomyocytes

o This takes intracellular Ca outside, in exchange for Na and is driven by the Na
gradient (Na is higher outside because of the Na-K-ATPase)
Digoxin inhibits the Na-K-ATPase, thus destroying the Na gradient by increasing intracellular
Na
o This means that the Na-gradient driven Ca-Na antiporter stops and thus intracellular
Ca is not transported out and Na builds up intracellularly due to Digoxins effect on
the Na-K-ATPase
Thus elevated Na and Ca intracellularly
Thus increased contractility (due to elevated available intracellular Ca)
Adverse Effects (see GLS apparently, is it a negative dromotropic drug??)
Narrow therapeutic index

Cause or worsen arrhythmias, many effects on ECG
Anorexia, nausea, vomiting, diarrhea, visual disturbances
Contraindications
Hyper/hypothyroidism
Interactions
Other drugs that slow cardiac contraction???

o I thought it increased contractility???
Drugs that cause electrolyte imbalances (hypokalemia)
Sinus Node Inhibitors

Examples
Ivabradine
Indications
HF, Angina
Decrease HR via block of I (funny) pacemaker currents in SA node thus decreasing HR

o The funny current is a mixed Na-K current that activates upon hyperpolarization (~-
40/-50 mV) and is responsible for initiating the depolarization phase of SA node
action potentials
o Inhibition of this current decreases HR and thus decreased oxygen demand
Inhibition of this current also increases the proportion of cardiac cycle in diastole (filling,
because no contraction because threshold hasnt been reached because inhibition of
current), which means improved coronary perfusion due (no constriction because no
contraction)
o Thus also used in angina
Neprilysin Inhibitors
Examples
Sacubitril
Indications
HF
Inhibits Neprilysin (an endopeptidase which degrades natriuretic peptides, bradykinin and
contributes to degrading ANG II) thus increasing natriuretic peptides effects
Also increases ANG II concentration (thus also administered with Valsartan, an AT1
antagonist remember?)
Produces vasodilation (decreased pre and afterload), increased GFR (decreased blood
volume), reduces SNS tone and aldosterone release, increases bradykinin levels
Adverse effects
Increases Alzheimers risk
Drug treatment for HT

Lifestyle advice for all patients
o Exercise
o Diet etc.
Anti-HTs in:
o Patients at low CVD risk (<10%) with persistent BP above 160/100 mmHg
o Patients at moderate CVD risk with persistent BP above 140/90 mmHg
Choice of drug:
o Patients with uncomplicated HT (no other co-morbidities)
ACE-I, AT1 antagonists, Calcium channel blockers and Thiazide diuretics
(main diuretic for HT) are first line
Monotherapy or in combination
Main classes of drugs used to treat HT:
o ACE-I
o AT1 antagonists
o Alpha-1 blockers
o Beta blockers
o Calcium channel blockers
o Diuretics
Drug Treatment of HF
Therapy with ACE-I (or AT1 antagonist) + beta blocker + diuretic (loop)/aldosterone
antagonist
Start low doses to avoid hypotension, hyper/hypokalemia
Remember Methyldopa contraindicated in depression (indicated in pregnancy) and ACE-I
and AT1 antagonists contraindicated in pregnancy
NSAIDs + ACE-I/AT1 antagonists + Diuretics = BAD
Exam type question:
Bill is prescribed a thiazide diuretic and a dihydropyridine, what are the cellular targets of
these drugs and where do they act
Thiazide Na-Cl co-porter in the DCT of nephron
Dihydropyridine L-type Ca channels in smooth muscle cells on vasculature

Week 4 Therapeutic Management of
Dysrhythmias and Atherosclerosis
Learning Objectives
DYSRHYTHMIAS
o Describe the ion fluxes involved in the phases of the action potential in
cardiomyocytes and Nodal cells
o Processes involved in Na channel activation and refractory periods in
cardiomyocytes
o Outline the cellular and ionic mechanisms responsible for the major types of
dysrhythmias
o Describe the cellular mechanism of action and the therapeutic rationale for the
different classes of drugs used in the treatment of dysrhythmias
o Explain the major adverse effects and important interactions and contraindications
associated with these drug classes
ATHEROSCLEROSIS
o Understand the basic pathophysiology of atherosclerosis as it relates to treatment
o Understand the function of major drug targets in the treatment of atherosclerosis,
such as HMG-CoA, PPARs etc.
o Describe the mechanism of action of statins and fibrates
o Understand the mechanism of action of ezetimibe, an inhibitor of cholesterol
absorption
o Understand why fish oil (omega-3 fatty acids) can be beneficial in atherosclerosis
Dysrhythmias and their treatment

What is Dysrhythmia?
Can result from a number of different mechanisms, but ultimately related to some ischemic
abnormalities, chronic heart failure or associated conditions
Dysrhythmia is an abnormal rhythm of the heart
o Palpitation or fluttering sensation of the chest
o Thumping sensation in the chest
After skipped beat next beat is much more forceful
o Racing heart
Causes inadequate blood to be pumped from LV to systemic circulation
Genetic Mutations and Polymorphisms

o Mostly K channels, but Na/Ca channel mutations may be important
o Relative minority of cases
Acute ischemia
o Main cause of dysrhythmia
Sympathetic stimulation
o Elevated NA/A have pro-dysrhythmic effect
Myocardial scaring
o Post-MI, scar tissue changes ability of cardiac tissue to conduct properly
Underlying Mechanisms
Automaticity Ability of heart to generate Aps on its own, without outside stimulus
o In heart, this automaticity can arise from pretty much anywhere SA node, AV
node, Myocardium etc.
3 major cellular level mechanisms
o Enhanced automaticity
Increase in frequency of depolarization in cells that normally display
spontaneous depolarization (SA, AV, His, Purkinje)
Or also in areas which lack spontaneous automaticity ventricular cells
(depolarization by ischemia)
o Triggered automaticity
Normal cardiac AP followed by abnormal depolarization
If the abnormal depolarization reaches a certain threshold, then there is a
secondary upstroke (abnormal, dysrhythmic beat)
2 main mechanisms
DADs Delayed Afterdepolarisations
o Caused by spontaneous release of Ca from Sarcoplasmic
Reticulum under conditions when there is too much Ca
intracellularly
o **Remember that there is that Na-Ca exchanger (see
Digoxin pharmacology in week 3 summary)?**
o The increased intracellular Ca levels drive the influx of Na
into the cell via the exchanger, this causes a depolarization,
a delayed afterdepolarisation
o This depolarization was not stimulated by a direct AP or
sinus activity, rather the incoming Na due to Ca
EADs Early afterdepolarisation
o Caused by interruption in phase 3 repolarization (when
there is K efflux, thus lowering membrane potential)
o Mostly different forms of K channels and other ion channels
contribute to this
o End result is extra beat after normal AP
o Re-entry
Anatomical
Occurs
when there is
myocardial
damage (scar
tissue)
This slows
the
conductance
This late
arriving
impulse can re-
activate an area of the heart that ha already depolarized, hence
causing a second depolarization, a re-entry
o If the impulse was not slowed it would have arrived at the
same location quicker and it would have been still in
refractory, but since it is slowed there is time for it to get
out of refractory and be excitable again
Functional
Didnt cover at all? But look at CVM notes from semester 1 if you
need to
Phases of Cardiac Action potential
Phase 4 Resting membrane potential

o Cardiomyocytes
Generated/maintained by various ion pumps including the Na-K-ATPase, Na-
Ca exchange and passive influx of K
o Pacemaker cells
In pacemaker cells phase 4 is a slow depolarization to threshold
Predominantly caused by increased influx of Na through voltage
gated channels (the funny channels) + increasing influx of Ca +
decreasing efflux of K
Phase 0 Rapid depolarization phase
o Cardiomyocytes
Caused by leak of influx of cations from adjacent cells via gap junctions
causing a slight depolarization in membrane potential
This triggers voltage gated Na channels to open and cause a rapid influx of
Na down its electrochemical gradient
o Pacemaker cells
Depends on activation of L-type Ca channels, NOT Na channels
Thus more gradual slope, because Ca influx
Phase 1 Notch
o Cardiomyocytes
Begins with inactivation of Na channels
Transient net outward current caused by efflux of K and Cl ions
Phase 2 Plateau phase
o Cardiomyocytes
Plateau is sustained by balance between influx of Ca (L-type channels) and
efflux of K
The influx of Ca is necessary for contraction
Contraction occurs
Phase 3 Rapid repolarization phase
o Cardiomyocytes and Pacemaker cells
L-type Ca channels close and efflux of K causes rapid repolarization
Major Classes of Anti-dysrhythmic Drugs
Vaughan Williams classification

o Classes I-IV
o Classifies drugs on basis of mechanism of action
Class I Na channel blockers
o Primarily interfere with phase 0 (rapid Na influx)
o Inhibit action potential propagation
Not only in heart, but other excitable tissue such as neural tissue
o Reduces maximum rate of depolarization during phase 0
o Use-dependence
Unique feature of class I drugs
Allows for targeting of Na channels of cells that are abnormally functioning
(not just a shotgun, all cells approach)
Activity of Na channels
Resting stage
o No ions going through
Activation/open stage
o Channel opens and allows Na ions to go through
o In response to depolarization
Inactivation/refectory stage
o Does not actively conduct Na ions
o But NOT ACTUALLY PHYSICALLY CLOSED
Na channel blockers must bind to the inside of the channel (not like cork on
a bottle), hence require the channel to be open to exert their effect
Thus the best opportunity is when the cell depolarization is
extended (when the Na channels are activated and open for longer
than usual)
In ischemic heart tissue (fucked/abnormal cells) the depolarization
phase is extended and the channel changes much more slowly from
activated to refractory then to resting
o This what we take advantage of when using Na channel
blockers, hence targeting the ischemic/abnormal cells
o 3 groups of Na channel blockers
Class Ia Procainamide
Association/dissociation kinetics is between Ib/c

No longer in common use
Prolongs repolarization (not as much as class III)
o HOW??
Class Ib Lignocaine
Fast association and dissociation
Equal affinity for activated and inactivated states
o Can get in when active or in refractory
Influenced only by the length of the AP
o If AP is longer, exert larger effect (because channels open
longer), such as in ischemic tissue
Rate of dissociation decreases during diastole (not systole because
Na channels are closed, see phase 2) if the membrane potential is
depolarized for longer, thus more blockade
Most effective (in depolarizing tissue, as Na channels are open)
o At high firing rates lots of open channels
o Diastolic phase (phase 4) is more depolarized
o In parts of the heart where the AP is longest
Clinical Use
o Used by IV infusion to treat and prevent ventricular
dysrhythmias post-MI
Complete first pass metabolism when administered
orally
o Half life ~2 hours
Can be influenced by factors effecting hepatic
circulation (like beta blockers reducing cardiac
contractility, hence decreased hepatic flow, hence
increased half life)
Also post-MI there is reduced CO, hence
longer half life
Hence dosage must be adjusted accordingly
o Adverse effects mostly due to effects on CNS
These drugs (as they are Na channel blockers) act on
excitable tissue
Drowsiness, disorientation, (if ODd) convulsions
Class Ic Flecainide
Very slow to associate and dissociate
o This suppresses almost everything else within the cell
They are pro-dysrhythmic
o All anti-dysrhythmic drugs are potentially dysrhythmic as we
are playing with ion channels
o So in wrong condition, can cause dysrhythmia
Clinically
o Very good at suppressing ventricular ectopic beats
APs coming from places other than SA node
Can come from excitable tissue (AV node, His,
Purkinje) or myocardium itself
o Very long acting
o Not used anymore after MI
o Main use is in suppressing ventricular ectopic beats and
prophylaxis against paroxysmal atrial fibrillation
Class II Beta adrenergic antagonists (Beta blockers)
o Interfere with phases 4 and 2
o Block effect of sympathetic neurotransmitters (hence need a SNS tone, otherwise
there is nothing to antagonize)
2 main effects of SNS on heart
Increases HR
Increases Contractility
o Phase 4 effect
Decreases pacemaker current
Thus decreasing HR
o Phase 2 effect
Decreases calcium currents
Decreases repolarizing K and Cl currents
Decreases Ca stored in SR, thus reducing spontaneous Ca release chances
and hence, reducing DADs
Thus, decreases contractility
o Antidysrhythmic effects by
Reducing HR
Decreasing intracellular Ca overload, inhibiting chances of DADs forming
o Clinically
Atria
Prevent paroxysmal atrial fibrillation when due to excessive
sympathetic activation
AV Node
Slows conduction through AV node, thus increases refractory period
of AV node, thus acts as a functional block
o So it only conducts a fraction of the atrial APs through to the
ventricle
Hence, if you had Supraventricular Tachycardia (SVT, very high rate
of depolarization in atria) you dont want to conduct every AP to
ventricle, hence by adding a functional block and increasing the
refractory of the AV node, only a fraction of the APs are conducted
o So used to prevent recurrent attacks of SVT
Ventricles
Ventricular dysrhythmias post-MI are partly the result of the huge
increase in SNS activity after an MI (because it is such a fucked
event)
o So if we block this increased SNS activity (via beta blockers),
then we can prevent ventricular dysrhythmias from
developing post-MI
Class III Drugs that prolong repolarization
o E.g. Amiodarone
o Mechanism of action is not clear
Most likely prolong repolarization by blocking K channels
Hence, also increased refractory period
This is the anti-dysrhythmic effect
By increasing refractory, the same area of tissue can not be excited
again, thus interrupting re-entry tachycardias and suppressing
ectopic activity
o Adverse effects
Photosensitive skin rashes
Thyroid abnormalities because structurally similar to thyroxine
Pulmonary fibrosis (late onset and irreversible)
Class IV Cardiac specific Calcium Channel Blockers
o Exert effect on phase 2
o E.g. Verapamil, Diltiazame
o Block voltage gated L-type Ca channels
Slows conduction in SA and AV nodes (because of slowing of phase 4 in
pacemaker cells) thus slowing generation of AP at SA node (HR) and
propagation of AP through AV node (partial AV block)
The partial AV block may terminate Supraventricular Tachycardias
Decreases Ca entry during phase 2 (in cardiomyocytes), hence reducing
chance of DADs and suppresses premature ectopic beats
Due to decreased Ca entry during phase 2 (thus shorter plateau) there is a
reduction in contractility (less calcium = less calcium for contraction)
o **Vascular specific L-type Ca channel blockers lead to reflex tachycardia due to
hypotension
This is pro-dysrhythmic
o Used prophylactically for paroxysmal SVTs
Drugs that do not fit into Vaughan Williams classification:

o Adenosine
Produced endogenously
Receptors
A1 Adenosine receptor SA and AV nodes
o Decreased cAMP negative chrono/dromotropy
Reduces calcium currents (because no
phosphorylation of Protein Kinase A), hence, delays
depolarization
Has exact opposite effects to SNS stimulation as SNS
stimulation would increase cAMP
Thus, reduction of Ca currents (thus less
chance of DADs), increased AV node
refractory period (thus can be used to
terminate SVT)
o Activates ligand gated (ACh) K channels in atrium and SA
node
Thus more K leaves cell (in phase 4), thus
hyperpolarization (2, in pacemakers), shortening of
AP duration (1, in pacemakers) and also slows the
rate of rise of the pacemaker potential (3, in phase
4) (see image below)
A2 Adenosine receptors Vascular Smooth muscle
o Increased cAMP, thus relaxation of smooth muscle, causing
vasodilation
Clinically
Administered IV to terminate SVTs
Adverse effects
Chest pain, shortness of breath, dizziness, nausea
Drug Interactions
Theophylline and other xanthine blockers (anti-asthma drugs)
o These block adenosine receptor (adenosine receptor
antagonists)
Dipyridamole (vasodilator and anti-platelet drug)
o Blocks reuptake of adenosine, potentiating adenosine and
prolonging its effects
o Cardiac Glycosides (DO THESE HAVE THE SAME MoA AS DIGOXIN??)

Mechanism of Action
Blocks Na-K-ATPase hence destroying the Na gradient across cell
(increase intracellular Na)
This effects the Na-Ca antiporter (pumps Ca out), hence build up of
Ca intracellularly, because no driving gradient
o This increased Ca is what causes increased contractility
Increases contractility
Pro-dysrhythmic effect
Because increased intracellular Ca and Na, increased phase 4 slope
in pacemakers, hence increased rate of automaticity
Anti-dysrhythmic effects (same as Adenosine, same as stimulating Vagus
nerve, same as dumping ACh)
Inhibit Ca currents in AV node (anti-dysrhythmic)
o Increases AV node refractory period
Activation of ACh mediated K currents in atria
o Hyperpolarization
o Shortening of atrial potentials
Clinically
Terminating re-entrant dysrhythmias involving AV node
Controls ventricular response in patients with atrial fibrillation
o Both because of AV node refractory period increase
Summary
Looking at the underlying mechanisms we can classify the drugs we have looked at:
o Enhanced Automaticity (HR)
4 ways to reduce the rate of spontaneous discharge
1. Decrease phase 4 slope
a. Beta blockers
2. Increase threshold
a. Na or Ca channel blockers
3. Increase maximum diastolic potential
a. Adenosine and ACh
4. Increase AP duration
a. Cardiac K channel blockers
o Triggered Automaticity (Ectopic beats)
Cause DADs and EADs
Reduction by drugs which interfere with the inward current (via Na or Ca
channels) responsible for these
o Re-entry (SVTs)
Anatomical Abnormal physical link between atria and ventricles
Fixed by blocking/prolonging propagation of AP
o Prolong AV node refractory period and slow AV node
conduction
Ca channel blockers (Class IV)
Beta blockers (Class II)
Cardiac glycosides
o Prolong AP
Class III (K channel blockers)
Functional Slowed conduction due to ischemic tissue
Fixed by prolonging refractory period of tissue
o Refractory period can be prolonged by delaying the recovery
of Na channels from inactivation
o Class I drugs Na channel blockers
Atherosclerosis and its treatment

Lifestyle modifications should ALWAYS be first step
o Diet + Lifestyle
Protein:Carbohydrates:Lipids ratio
Smoking + exercise
o 6 months to determine impact
Major Drug Classes to treat Dysli pidemia
More or less decrease circulating LDL, but through different ways

HMG-CoA reductase inhibitors Satins
o Drug of choice to lower cholesterol levels
o Examples
Simvastatin, lovastatin etc.
o Cholesterol Synthesis
Acetyl CoA HMG-CoA Mevalonate Cholesterol
^
HMG CoA reductase
o HMG-CoA reductase inhibitors have a Mevalonate-like side-chain, hence the enzyme
recognizes it as too much Mevalonate, thus inhibiting production of endogenous
cholesterol
But that isnt usually the issue, the issue is dietary cholesterol
So to reduce this, it is indirect
o The actual mechanism is:
HMG CoA reductase inhibiting endogenous cholesterol production
This causes low endogenous cholesterol within hepatocytes (intracellularly)
This signals transcription factor (SREBPs) to translocate into nucleus and
activate expression of LDL receptor gene (upregulate receptors)
These receptors bind to cholesterol in blood (dietary) and brings them into
cell to normalize the endogenous cholesterol levels
o Cardioprotective effects other than lowering LDL

Endothelial function
Enhances production of NO (vasodilator)
Increases stability of plaques
Metalloproteinases weaken fibrous cap, therefore bad
Statins inhibit production of metalloproteinases by macrophages
Anti-Inflammatory effect
Identified by decrease in C-reactive protein biomarkers
o Adverse effects and toxicity
Hepatotoxicity can occur
Doesnt cause liver failure though
Myopathy (leading to rhabdomyolysis)
Major adverse effect of statin use
Interactions with fibrates elevates statin levels
Bile acid binding resins
o Cholestyramine and Colestipol
Not absorbed from the intestine, taken orally and stay in GIT
Safe
o They bind bile acid
Bile acid is full of cholesterol
o This prevents reabsorption of cholesterol
o Adverse effects
Interfere with absorption of acidic and fat soluble vitamins, thyroxine,
barbiturates, some anti-inflammatories
Often requires concomitant use of laxatives due to constipation and bloating
Nicotinic Acid Niacin
o Water soluble vitamin B-complex that functions as a vitamin after activation in the
body (conversion to NAD or NADP)
o Effects
Increases HDL-Cholesterol (30-40%)
Lowering triglycerides (35-45%)
Reduces LDL-Cholesterol (20-30%)
o Mechanism of Action Adipocyte
Activation of inhibitory GPCR
Decrease adenylyl cyclase
Decrease cAMP
Decrease triglyceride synthesis
Decrease Free Fatty Acid release
Decrease triglyceride lipolysis
o Mechanism of Action Liver

Reduction of triglyceride synthesis reduction of LDL
Enhanced Lipoprotein Lipase activity clearance of chylomicrons and VLDLs
Raises HDL-C levels
o Mechanism of Action Macrophages/monocytes
Stimulates expression of cholesterol transporter
Net effect is HDL-mediated reduction of cellular cholesterol content
o Adverse effects
Flushing and pruritus of the face and upper trunk
Likely Prostaglandin mediated
Dyspepsia (indigestion), nausea, vomiting, diarrhea
Fibric acid derivatives Fibrates

o Clofibrate, fenofibrate, bezafibrate etc.
o Mechanism of Action
Agonists of PPAR-alpha receptors
Activation of transcription factors (similar to statin mechanism)
which upregulate LDL receptors, hence lowering blood LDL
Stimulates apoA-I and apoA-II expression
o Leads to increase HDL
Stimulation of fatty acid oxidation, increased LPL synthesis and
reduced expression of apoC-III
o Leads to decrease in Triglycerides
o Non-hypolipidaemic effects
Anti-thrombotic effects
Inhibition of coagulation
Enhancement of fibrinolysis
o Adverse effects
Myositis
May lead to renal failure
Increased bile production
Due to increased turnover of lipoproteins
May lead to gallstones
The cholesterol absorption inhibitors
o Example Ezetimibe
o Inhibits dietary cholesterol absorption by enterocytes in the small intestine to lower
total and LDL cholesterol
Inhibits transport protein NPC1L1 (at jejunal enterocytes)
Thus blocks absorption of cholesterol
Week 5 Drugs for Homeostasis
Learning Objectives
Outline the normal physiological processes involved in haemostasis and thrombosis,

including platelet activation and aggregation, and the coagulation cascade
Describe the role of arterial and venous thrombi in ischemic heart disease, stroke and
pulmonary embolism
Explain the cellular mechanism of action of the different classes of anticoagulants,
thrombolytic and antiplatelet drugs
Outline the therapeutic rationale for the use of these drugs in thrombotic disorders
Explain the importance of drug monitoring when using warfarin
Describe the major adverse effects, contraindications and important diet/drug interactions
associated with anticoagulants, thrombolytic and antiplatelet drugs
Hemostasis
Balance between Coagulation and Fibrinolysis

Virchows Triad
Injury to blood vessel wall

o E.g. Atherosclerosis, aneurysm
Changes to blood flow
o Atrial fibrillation
o Stasis of blood sitting down for long time may lead to DVT
Changes to Coagulability
o During pregnancy
o Certain drugs (oral contraceptives estrogen)
o Conditions of excess blood cell formation (e.g. polycythemia vera)
Antithrombotic agents
Thrombus = Fibrin + Platelets

o Anticoagulants Inhibit fibrin formation
Heparin, Warfarin, Thrombin inhibitors
o Fibrinolytics Degrade fibrin
If fibrin has already formed
Streptokinase, Alteplase
o Antiplatelet drugs Inhibit platelet activation or aggregation
Aspirin, Adenosine, Glycoprotein IIB/IIIA receptor antagonists, Prostanoids
Anticoagulants
Heparin
Cannot be administered orally either IV or SC

Endogenous molecule
o Produced by mast cells together with histamine
Mechanism of Action
o Potentiates activity of Antithrombin III (ATIII)
No intrinsic coagulation effects (acts indirectly via ATIII)
Binds to and accelerates ATIIIs inhibitory effects on different coagulation
proteases
Inhibits Thrombin activation
Inhibits factor Xa, IXa, XIa, XIIa (all of intrinsic pathway + Xa)
Rapid onset of action

Common risks
o Hemorrhage
o Thrombocytopenia (immune mediated)
IgG or IgM antibodies against Heparin + Platelet factor 4 complex
Other side effects
o Hypoaldosteronism
HEP can inhibit aldosterone synthesis Hyperkalemia
Osteoporosis, allergic reactions
Low Molecular Weight Heparins (LMWHs)
o Too small to interact with Thrombin
o Targets factor Xa
o Advantages of full size Heparin

Easier to administer than full size heparin (SC by patient)
Longer half life
Reduced need for blood monitoring more predictable and reliable
Avoiding development of hemorrhaging
Warfarin
Analogue of Vitamin K
o Vitamin K required for synthesis of prothrombin, factors II, VII, IX and X
o Vitamin K alternates between oxidized and reduced state which is catalyzed by
Vitamin K reductase and Vitamin K carboxylase
Mechanism of Action
o Competes with Vitamin K for Vitamin K reductase
Hence decreased functional coagulation factors
o Delayed onset
It takes several days for degradation of existing functional coagulation
factors
o Antidote = Vitamin K (for warfarin poisoning)
Isoforms
o S-Warfarin is 3-4 times more potent than R-Warfarin
Metabolism
o Metabolized in Liver by CYP2C9 enzyme
Potential problems with Warfarin
o Diet, alcohol consumption, body mass, concomitant medications, co-existing
disease, genetics
o Hence, high degree of variability between patients
o Genetics
Polymorphisms in 2 genes can effect Warfarin efficacy
CYP2C9 S-Warfarin metabolizing enzyme
o Variants affect pharmacokinetics
Enzyme becomes more active, hence less Warfarin
activity
VKORC1 Gene encoding for Vitamin K reductase
o Variants affect pharmacodynamics
o Risk of hemorrhage
Decreased metabolism due to CYP2C9 inhibition
Lots of drugs do this, e.g. Amiodarone
Relative deficiency of Vitamin K (via antibiotic abuse for example)
Adding Warfarin will increase the already increased risk of
Hemorrhage due to low Vitamin K
o Displacement from protein binding sites reduces efficacy
By loop diuretics for example
o Birth defects and abortion
First trimester Bone defects
Second and third trimester CNS defects
Foetal hemorrhaging, thus death may occur
Hence, Vitamin K antagonists are contraindicated during pregnancy
Thrombin Inhibitors
Direct thrombin inhibitors

2 classes
o Hirudin-like molecules
Binds irreversibly to Thrombin
o Serine protease inhibitors (2 forms)
Dabigatran direct Thrombin inhibitor
Rivaroxaban Inhibitor of factor Xa
Antiplatelet Drugs
Aspirin
Mechanism of Action
o Irreversible inhibitor of Cyclo-oxygenase (COX)
COX converts Arachidonic Acid (AA) to Prostaglandins, Prostacyclins and
Thromboxanes
o Thus, prevents Thromboxane formation
Thromboxane acts as a platelet aggregator
o Thus, prevents platelet aggregation
o Also platelets dont have a nucleus, thus once COX enzyme is inhibited the platelet is
fucked (cant make more COX), so platelets are more susceptible to COX inhibition
than other cells (like endothelial cells)
Doses have near-selective effect on platelets
o 100-300mg Platelet aggregation
o 600-900mg Headache
o 5,000mg Inflammation
Aspirin (and other NSAIDs) non-selectively bind to COX enzymes (either 1 or 2)
o COX 1 Housekeeper
This is the one we dont really want to interfere with as it produces a variety
of prostaglandins involved in many physiological responses
It is constitutive (always active)
o COX 2 Inflammatory mediator
This is the one we want to target to have the anti-inflammatory effect of
NSAIDs
It is inducible (induced when needed) hence non-selective NSAIDs need
high doses to inhibit this (thats why aspirin has anti-inflammatory effects at
high doses)
o There are drugs that are selective for COX 1 or 2 and COX 2 inhibitors (coxibs) are
used for people with high risk of GI problems (see image below)
Adenosine (same as last weeks adenosine)
Anti-platelet drugs work because they increase the production of cAMP in the platelets
o The elevated cAMP opposes platelet aggregation physiologically
Mechanism of Action
o Acts on A2 adenosine receptors to increase intracellular cAMP
Elevated cAMP facilitates transport of intracellular calcium into storage pool
(for example SR)
Thus, decrease in intracellular Ca
Thus, decreased platelet aggregation
As Adenosine is endogenous, above is a physiological process

o So drugs (below) can target/potentiate this to inhibit platelet aggregation
Dipyridamole
Blocks Adenosine reuptake into cell
PDE inhibition cAMP degradation decreases
Thus, more platelet aggregation because more cAMP
ADP binds to P2Y12 (another Adenosine receptor) to decrease cAMP (*but this is does not
effect platelet aggregation) and activates GP IIb/IIIa (this is what allows for platelet
aggregation)
o Hence, in contrast to Adenosine, ADP is a pro-coagulant/pro-platelet aggregator
Clopidogrel
Antagonist of ADP by binding to P2Y12 receptors
Thus, inhibiting the ADP-mediated process of activating GP IIb/IIIa, thus
inhibiting platelet aggregation
Glycoprotein IIb/IIIa receptor antagonists
Fibrinolytic Drugs
Fibrin formation and breakdown
Streptokinase
Mechanism of Action
o Potent Plasminogen activator coverts it to Plasmin
Widely used in treatment of acute MI

However, potentially problematic in NQ and NT
o High prevalence of Beta-hemolytic streptococci (where Streptokinase comes from)
infections
o These individuals already have antibodies against Streptokinase
o Hence, no point giving Streptokinase to this population as they are more or less
immune
Thus, tPAs are preferred (but are more expensive so just double the dose)
Tissue Plasminogen Activators
Serine proteases
o Digest fibrin, fibrinogen, factors II, V and VII
Very specific
o More active on fibrin-bound plasminogen than on plasma plasminogen
Hence clot-specific
Week 6 Endocrine and Reproductive
Pharmacology
Learning Objectives
GENERAL
o To apply the concept of feedback regulation in endocrine systems for the
identification of the pathophysiology of endocrine disorders
o To identify the central and peripheral regulations of hormone secretion
o To summarise the mechanisms of action of the hormones (peptide-, glycoprotein-
and steroid hormones)
THYROID & GLUCOCORTICOIDS
o Outline the main features of hyper- and hypothyroidism
o Describe the mechanism of action of carbimazole and methimazole
o Analyse the side-effects of drugs used in the treatment of thyroid diseases
o Describe the therapeutic use and side-effects of glucocorticoids, e.g., Addison
disease, asthma, etc. on the basis of their physiological effects
REPRODUCTIVE HORMONES
o To understand the mechanisms of action of oral contraceptives
o To understand the potential benefits, side-effects and possible complications that
can emerge from the administration of hormone replacement therapy after
menopause
o To be familiar with the pharmacological use of androgen steroids
o To understand the risks associated with the use of anabolic steroids for performance
enhancement
Thyroid Disorders and Pharmacology

General therapeutic approach to hormone disturbances
Hypo state (reduced)

o Hormone replacement therapy
Hyper state (too much)
o Block synthesis
o Block release
o Block effects
If we introduce a hormone (exogenous) the body may decode this as an overproduction of
the endogenous hormone and shut down that axis, leading to hypo states of the hormone
Hyperthyroidism and pharmacotherapy
Symptoms
o Excessive thyroid secretion high metabolic rate, increased skin temperature,
nervousness, tremor, tachycardia, increased appetite with weight loss
Types
o Graves Disease
Autoimmune condition Stimulatory auto-antibodies against TSH receptors
Hence, more T3, T4
High iodine content potentiates
Pharmacotherapy
o Radioiodine
Almost all Iodine we consume ends up in the thyroid gland
So radioactive I is administered and when it accumulates it starts kills
thyroid cells
Has variable results
o Thioureylenes Carbimazole, Methimazole
Mechanism of Action
Inhibit iodination of thyroglobulin
Thus inhibit the synthesis and thus output of T3, T4
Doctors generally look at TSH levels to determine efficacy of treatment as
they should rise due to the decreased inhibition by T3, T4
Pharmacokinetics
Oral administration
Rapid inhibition of Thyroid hormone production, but clinical effects
take weeks
o Due to long half life of Thyroid hormones
Adverse effects
Neutropenia and possible agranulocytosis
o Reversible with cessation of treatment
Hypothyroidism and pharmacotherapy
Symptoms
o Decreased activity of thyroid low metabolic rate, slow speech, deep and hoarse
voice (because edema in vocal chords), lethargy, Bradycardia, cognitive impairments
Hashimotos Thyroiditis
o Autoimmune origin auto-antibodies against thyroglobulin (required for synthesis
of T3, T4)
Pharmacotherapy
o No specific treatment to increase synthesis or release
o Hormone replacement therapy Levothyroxine (T4), Liothyronine (T3)
Levothyroxine is first choice
Identical to Thyroxine
Oral administration
Overdose mimics hyperthyroidism
Glucocorticoid Pharmacology
Cortex
o Steroid hormones Glucocorticoids and Mineralocorticoids
Medulla
o Adrenalin
Glucocorticoids
Mechanism of Action
o Steroid hormone, thus bind to intracellular receptors
o Together, the receptor-hormone complex acts as transcription factors which travel
into the nucleus
o Here the complex binds to a steroid response element within the intron of the
particular gene of interest
o Thus changing the genes expression (increase or decrease expression)
Asthma
Glucocorticoids can increase the expression (upregulate) beta 2
receptors using the above mechanism
o Basic transactivation up regulation of transcription (increase expression)
o Basic transrepression displacement of transcription factors (decrease expression)
Potent anti-inflammatory agents and immunosuppressants (in higher doses)
o E.g. used in preparation for organ transplants
Use high doses of glucocorticoids to suppress immune response of the body
in order to successfully transplant
Could use endogenous compound, but synthetic molecules are better practically
o Better oral absorption
o More activity on skin
o Alter affinity for mineralocorticoid receptors
Endogenously they can bind,
Therapeutic effects of Glucocorticoids
o Hormone replacement
Management of adrenocortical insufficiencies (e.g. Addisons disease)
Addisons Disease
o Deficiency of corticosteroid (gluco/mineralocorticoids)
production
o Autoimmune damage to adrenal cortex (mainly)
o Muscle weakness, low BP, hypoglycemia,
hyperpigmentation of skin, electrolyte disorders
(hypernatremia and hypokalemia)
o Inflammatory and immune disorders
Asthma, rheumatoid arthritis, immunosuppression
Asthma (fluticasone, budesonide, mometasone)
Reduce expression of cytokines (same mechanism of action outlined
above)
Reduce inflammation associated with asthma and other respiratory
conditions
Inhibits COX2 inhibition of PGE2 and PGI2, hence vasoconstriction
and reduce immune cell migration and vascular permeability
(reduce oedema)
Upregulation of beta 2 receptors
Reduced mast cell activation suppression of the inflammatory
reaction all together
o Prolonged administration of high doses of glucocorticoids iatrogenic Cushing
syndrome
o Sudden cessation of glucocorticoid treatment leads to hypofunction
Must be gradually tapered down
Reproductive Pharmacology
Oral Contraception
Goal is to prevent ovulation

2 major forms
o Combined Estrogen + Progestin
Estrogen component ethinyl estradiol or metranol
Progestin component levonorgestrel
Essentially, tricks the negative feedback of the body into thinking that there
is high circulating levels of these hormones (just like in pregnancy) thus we
dont want to ovulate (development and release of ovum) hence,
preventing ovulation
Ovulation is preceded by and likely to be caused by the pre-ovulatory LH
surge
This mid-cycle LH surge is absent in combined contraceptives
Mechanism of action
Hypothalamic action
o Progesterone suppresses the increasing pulsatile secretion
of GnRH prior to ovulation
o This increasing frequency of pulsatile secretions signals LH
production and secretion, thus without these pulses,
decreased LH synthesis and secretion
Pituitary action
o Decrease pituitary sensitivity of GnRH
o Estrogen suppresses FSH release during follicular phase
o Progesterone inhibits estrogen-induced mid-cycle LH surge
Decreased sperm transport in fallopian tube
o Progesterone produces thick, viscous mucus in the cervix
o Progestin-only
For women where estrogens are contraindicated
Usually do to high circulating estrogen increasing risk of venous
thrombosis
Block ovulation in only 60-80% of cycles
Mechanism of Action
Same progesterone actions at hypothalamus and pituitary
Thickening of cervical mucus
o Decreased sperm motility
Endometrial alteration
o Causes impaired implantation
Medroxyprogesterone acetate very strong progesterone-like drug
Blocks GnRH pulses at hypothalamus and inhibits ovulation
Menopause
Due to diminishing concentration of estrogen (mainly) and also progesterone

o Due to atrophy of ovaries
Symptoms (due to low circulating estrogen and progesterone)
o Vasomotor flushes
Chilly and hot flushes alternate
Due to lack of regulatory effect of estrogen on vasomotor tone
o Vaginal dryness
o Urinary symptoms
Estrogen and progesterone have effects on bladder lining
o Osteoporosis
Thinning and weakening of bones
Due to lack of pro-osteoblastic activity of estrogen
o Coronary heart disease
o Cardiovascular effects
Whole host of effects can lead to increased Atherosclerosis leading to IHD
Solution
o Hormone replacement therapy
Estrogen alone
Increased risk of endometrial carcinoma
Estrogen + progesterone
Progesterone used to mitigate some of the deleterious effects of
estrogen by
o Decreased estrogen receptor content
o Increasing local conversion of estrogen into a less active
metabolite
Should be used for treatment of menopausal symptoms for shortest
possible time
Estrogen receptor antagonists
o Selective estrogen receptor modulators (SERMs)
Tamoxifene, raloxifene
Not full antagonists/agonists
Used if someone is needed for chronic estrogen receptor inhibition due to
hormone sensitive tumor (breast cancer, endometrial cancer)
Use antagonist for breast cancer
Agonist for osteoporosis
You can also get tissue-selective estrogen agonist/antagonist activity
Agonistic or antagonistic activity depends on
Relative expression of the 2 forms of estrogen receptors, alpha and
beta (ER)
o So different cells can have different responses (stimulatory
or inhibitory) with the same SERM
Ligands effect on the receptor structure conformational changes
Availability of co-factors (co-activators or co-repressors)
o Anti-estrogens (full actual antagonists)
Clomiphene
Block the receptor (endogenous estrogen cannot bind to it)
Thus, blocking the effects of estrogen
Large increase in GnRH, LH and FSH (because body thinks no
estrogen, so need to stimulate)
o This is a way to induce ovulation (because LH surge)
Infertility treatment

o Selective estrogen receptor down regulators
Fulvestrant
Destabilizes the estrogen receptor and facilitates its degradation
Dont bind to the receptor, rather, get rid of the receptor
End result is the same
Increased proteolytic activity of ER-alpha but not beta
Effective in Tamoxifene resistant breast cancer
Estrogen sensitive tumor cant grow in these conditions
Men
Pharmacological use of androgens (agonists)

o Virilising effects
For male hypogonadism
o Anabolic effects
Catabolic and wasting state
Muscle wasting associated with AIDS
Increase muscle mass and strength
Enhancement of athletic performance
Side effects
o Suppresses endogenous testicular function
o Angioedema
Due to genetic impairment of C1 esterase inhibitor (C1EI)
C1EI inhibits kallikrein which produces bradykinin
Hence, build up of bradykinin leading to increased vascular
permeability and thus submucosal and subcutaneous edema of
respiratory and GIT
Androgens stimulate hepatic synthesis of C1EI, thus decreased bradykinin
and angioedema
Androgen receptor antagonists (flutamide)
o Alone, limited efficacy due to LH production and subsequent increase in T which will
compete out the antagonist
Thus given in conjunction with GnRH analogue so we can desensitize GnRH
receptors in pituitary, inhibiting downstream effects
o Clinically
Metastatic prostate cancer
Testosterone sensitive tumor
Hirsutism abnormal hair growth in women
5 alpha reductase inhibitors (finasteride)
o 5 alpha reductase converts testosterone to dihydrotestosterone (more active)
5 alpha reductase inhibitors block this
o Clinically
Benign prostatic hyperplasia
Benign enlargement of prostate (not cancer)
Responsive to decreasing circulating testosterone levels
Male pattern baldness
Decreasing DHT somewhat alleviates
o Side effects
Impotence
Oxytocin
Mechanism of Action
o Acts on GPCR (OXT receptors) activating PLC-IP3-Ca signaling pathway
o Elevated intracellular Ca
o Smooth muscle contraction
o Increases local prostaglandin production in uterus
Further stimulation of uterine contractions
Clinically
o Agonists (Pitocin)
Labour
Induction
o Antidiuretic effect
Augmentation
o Overstimulation can cause trauma of the mother and fetus
Postpartum hemorrhage
o Uterine contraction reduces bleeding
o Antagonists (Atosiban)
Preterm Labour
To inhibit contractions
Week 7 Diabetes and Obesity
Pharmacology
Learning Objectives
To understand the pathophysiology of diabetes mellitus (Type 1 and Type 2) in order to
better appreciate how drugs work
Identify the primary targets of the different hypoglycaemic agents
Outline how the effect of the drugs on their primary target translate into therapeutic
benefits in diabetes
Compare and contrast the mechanisms of action of oral hypoglycaemic drugs
To understand the side-effects hypoglycaemic drugs
Understand the metabolic basis of obesity
Apply this mechanistic understanding to explain mechanism of action of recently introduced
anti-obesity drugs
Be familiar with non-pharmacological modifications that can be used in conjunction with
pharmacological means to combat obesity
Diabetes Pharmacology
Patho/physiology
Diabetes Mellitus
o Spectrum of metabolic disorders with a variety pf pathogenic mechanisms
o Genetic and environmental factors contribute
o Hyperglycaemia is the central feature
o Aetiology
Insufficient insulin secretion key feature of Type 1
Reduced responsiveness to endogenous or exogenous insulin key feature
of Type 2 (later onset)
Receptor issue
Increased glucose production
Abnormalities in fat and protein metabolism
o Chronic Hyperglycaemia causes
Retinopathy
Neuropathy
Nephropathy
CV diseases like atherosclerosis
Glucose homeostasis
o Fasting state (no food for 8 hours)
Glucose is supplied primarily by liver and fatty acids from adipose tissue
Hepatic glycogenolysis and gluconeogenesis
Low insulin
Releases adipocytes from inhibition increased fatty acid oxidation
for gluconeogenesis
Increased glucagon
o Prandial state (after eating)
Increased plasma glucose
Incretins released from gut increase insulin secretion
Attempt to decrease circulating glucose
Skeletal muscle and adipose tissue glucose uptake increased
o Increased glycolysis (glucose oxidation)
Hepatic glucose production and lipolysis decreases
Stressors activate SNS and through beta receptors, stimulate insulin release
PNS stimulates insulin secretion
Pancreatic Beta cells
o Endocrine cells produce, store and release insulin
o In resting state (fasting) hyperpolarised
Because ATP-sensitive-K channels are open hence K efflux
hyperpolarisation
Inhibited state no insulin release
o Prandial state increased circulating glucose
Glucose enters cell
Glycolysis occurs and produces ATP
Increased ATP closes ATP-sensitive-K channels
This causes increased K inside depolarisation
Depolarisation opens voltage gated Ca channels
Induces exocytosis of stored insulin
Type 1
o Autoimmune-mediated destruction of pancreatic beta cells
o Leading to total or near total insulin deficiency
Type 2
o Complex, heterogeneous syndrome impaired insulin secretion and insulin action
o Overweight or obesity commonly precipitates
o Insufficient insulin action to maintain normal plasma glucose levels
Insulin production is reasonably alright
Regardless of presence of insulin, cells cannot take up glucose
hyperglycaemia
Therapeutic goals
o To alleviate the symptoms related to hyperglycaemia
Neuropathy, nephropathy, vascular damage etc.
o Prevent or reduce the acute and chronic complications of diabetes

Treatment of Diabetes
Overview of the classes of drugs
o Parenteral hypoglycaemic drugs
Insulin and other injectable drugs
Incretin-mimetic drugs GLP-1 agonists, exenatide
o Oral hypoglycaemic drugs
Biguanides (e.g. Metformin)
Sulfonylureas and other drugs that stimulate insulin secretion (e.g.
Tolbutamide, glibenclamide, nateglinide)
Thiazolidinediones (e.g. Pioglitazone)
Gliptins (e.g. Sitagliptin)
Alpha-Glucoside inhibitor
Insulin
Peptide hormone short half-life (10 minutes)

o Usually subcutaneous administration (because broken down by GIT peptide)
When given not just insulin alone due to short half-life and changing daily needs of insulin
o Formulations of insulin try
To avoid wide fluctuations in plasma glucose concentration and blood
glucose downregulates receptors
Different formulations vary in the timing of their peak effect and duration of
action
o Different formulations
Short-acting preparations soluble insulin and insulin lispro
Acts more rapidly, but for shorter period than natural insulin
o Patients can inject just before large meal by the time
glucose goes up, insulin forces it into cells
Intermediate-acting preparations Isophane insulin and Insulin zinc
suspensions
Insulin is slowly absorbed
Long-acting preparations Insulin glargine
Provides constant basal insulin supply (resting level insulin)
Can be used in conjunction with short-acting just before meals or
before activities
Clinical uses
o Type 1 diabetes require long-term insulin
Intermediate or long-acting combined with short-acting before meals
o Type 2 diabetes 1/3 of patients benefit from insulin
o Hyperglycaemic emergencies (e.g. Diabetic Ketoacidosis) Immediate-acting soluble
insulin
Intravenously administered
DKA (generally in T1 diabetes) hyperglycaemia, cells starve, fatty acid
breakdown, elevated ketones, acidic blood, metabolic acidosis
(compensatory respiratory alkalosis via hyperventilation)
o During intercurrent events (e.g. things that drive up the stress response infections,
MIs, operations etc.) patients with type 2 diabetes or impaired glucose tolerance
administered short-term insulin treatment
o Gestational diabetes if not controlled by diet
o Hyperkalaemia emergency treatment
Insulin + glucose drives K into cell, lowering extracellular K
Essentially fuelling the Na-K-ATPase
Incretin-mimetic Drugs
Incretins (Glucagon-like peptide 1, GLP-1)

o Produced by cells in GI system
o Functions
Stimulate insulin release; Inhibits glucagon release
Lowers blood glucose
Slows gastric emptying
Reduces food intake increased satiety (decreased hunger)
Reduces hepatic fat accumulation
o Exendin-4 acts like GLP-1 (incretin agonist)
Disables prey by rendering them hypoglycaemic
o Exenatide synthetic version of exendin-4
Mimics incretins, but longer-lasting
Effects lowers blood glucose via
Increases insulin secretion
Inhibits glucagon secretion
Slows gastric emptying
Biguanides (e.g. Metformin)
Reduces hepatic glucose production

o Decreased gluconeogenesis (increased in T2 diabetes)
Mechanism of Action
o Activation of AMP-activated protein kinase (AMPK)
Results in an increase in a nuclear receptor which inhibits the expression of
genes important for gluconeogenesis
Decreased gluconeogenesis decreased glucose output
o Increased glucose uptake and utilisation in skeletal muscle (reduce insulin
resistance)
o Reduced carbohydrate absorption in GIT
o Increased fatty acid oxidation
o Reduce circulating LDL and VLDL
o Anorectic effects decrease food intake
Systemic hormonal effects
Increased leptin sensitivity (increased satiety)
Decreases ghrelin (ghrelin decreases satiety)
Increases incretin (GLP-1) levels
Hypothalamic effects
Increases alpha-MSH (increases satiety)
Decreased NPY (increased satiety)
Sulfonylurea Drugs (e.g. Tolbutamide,

Glibenclamide, Glipizide)
Act on Sulfonylurea receptors (SUR) to stimulate

release of insulin
Mechanism of Action (mimic high ATP intracellularly)
o SUR found on ATP-sensitive K channels
o Bind to SUR on these channels
o Inhibit hyperpolarising K efflux
o Depolarisation
o VGCC open for Ca influx
o Insulin released via vesicle exocytosis
Other drugs that lack the Sulfonylurea structure, but block SUR
o E.g. Repaglinide, Nateglinide
o Rapid onset/offset kinetics short duration of action and low risk of hypoglycaemia
o More specific to SUR on pancreatic beta cells
o If given before meal reduce postprandial rise in glucose in T2 diabetes
Thiazolidinediones (e.g. Pio glitazone)
Reduce hepatic glucose output decreased gluconeogenesis, glycogenolysis

Enhance effectiveness of endogenous insulin increase glucose uptake into muscle
Mechanism of Action PPAR-gamma agonist
o Bind to PPAR-gamma receptor (intracellular nuclear receptor)
Mainly in adipose tissue
o Dimerises with retinoid-X receptor to from PPAR-gamma-RXR complex
o Translocates into nucleus
o Influences transpiration of genes important in insulin signalling
Actions
o Causes differentiation of adipocytes weight gain by increased subcutaneous fat
o Increased lipogenesis
o Enhanced uptake of fatty acids and glucose
Gliptins (e.g. Sitagliptin, vildagliptin)
Mechanism of Action
o Competitive inhibitors of Dipeptidylpeptidase-4 (DPP-4)
Responsible for deactivation of incretins
o Hence, potentiates endogenous incretins
o Lowering blood glucose
Stimulate insulin release
Inhibiting glucagon release
Weight neutral no weight gain/loss
Alpha-glucosidase inhibitors (Acarbose)

Alpha-glucosidase breaks down starch and disaccharides into glucose
o In brush-border of SI
Hence, decrease production of glucose via metabolism of starch and disaccharides
o Slows absorption of carbohydrates from GIT blunts postprandial glucose increase,
essentially lowers glycaemic-index of foods
Postprandial peak is not good for diabetes management, this allows it to be
controlled
Increases the release of incretins glucose-lowering effect
Side effects related to persistence of disaccharides and starches
o Flatulence (due to fermentation in LI by bacteria)
o Loose stools water follows sugar (osmotically active)
Summary table
SGLT2-inhibitors (e.g. Dapagliflozin, Canagliflozin)
SGLT1 in brush-border of SI
SGLT2 in kidney nephron
o 90% of glucose reabsorbed by SGLT2 in nephron (10% by SGLT1 in nephron)
High plasma glucose (diabetes)
o SGLT2 up-regulation (to compensate and increase glucose reabsorption)
o When filtered load exceeds capacity to reabsorb it leads to glycosuria (+water),
hence, polyuria and polydipsia
Mechanism of Acton of SGLT2-inhibitors
o Prevent reabsorption of glucose via
cotransport with Na in proximal tubule of
nephron
Effects
o Genito-urinary infections (glycosuria
provides bacteria with glucose)
o Modest weight loss
o No hypoglycaemia (lets out only as much
glucose that is filtered from blood)
o BP reduction (polyuria hypovolemia)
Obesity Pharmacology
Obesity
Complications
o CV Hypertension, dyslipidaemia
o Respiratory Asthma, obstructive sleep apnoea
o Endocrine Diabetes
o GI Gallstones, reflux oesophagitis
Management
o Weight loss
Lifestyle modification
Diet
o Weight maintenance
Lifestyle modification
Pharmacotherapy
o Bariatric surgery
Regulation of food
o Takes place in hypothalamus
Arcuate nucleus
Stimulatory group of neurons (increase food intake)
o Main stimulatory factors Neuropeptide Y (NPY) and Ag
Related protein (AgRP)
Inhibitory group of neurons (decrease food intake)
o Main inhibitory peptide POMC
o 5HT2c receptors present
o Satiety signal Leptin
Produced by adipose tissue
Stimulates inhibitory group of neurons in arcuate nucleus Im full
Coded by ob gene and receptor coded by db gene
Most obese people have high leptin (a consequence, rather than cause)
Hence, really only useful if you have no leptin (ob/ob) or no receptor
(db/db)
Discontinued Pharmacotherapy
Rimonabant
o CB1 Cannabinoid receptor antagonist
When you smoke a phat bowl you get the munchies via this receptor
o Withdrawn in 2008 because of adverse effect on mood in some patients
Suicidal ideations
Sibutramine
o Inhibits reuptake of serotonin (5-HT) and NA at the hypothalamic sites that regulate
food uptake
o Withdrawn because cardiovascular risks outweighed its benefits
Pharmacological management of obesity
Orlistat
o Lipase enzyme inhibitor in stomach and intestines
Intestinal fat digestion reduced
Cannot absorb long-chain, large fat molecules
Less calorie intake from lipids (not absorbed)
Weight loss
o Relatively safe as we are blocking absorption so no real systemic side effects
GI- side-effects related to high concentration of fat in stool
Lorcaserin
o Selective 5-HT2c agonist
Increases activity of inhibitory neurons of arcuate nucleus
Increased alpha-MSH production
Acts on MCR4 in paraventricular nucleus
Reduced food intake
Phentermine
o Amphetamine-like psychostimulant
Indirect sympathomimetic
Inhibition of vesicular monoamine uptake
Prevents neurotransmitter reuptake into vesicle
o Inhibits VMAT
More non-recyclable NA/Dopamine in presynaptic terminal and thus
entering synaptic cleft
Activation of Trace amine-associated receptor 1 (TAAR1)
Stimulate vesicular release
Also increase NA/Dopamine this way
Increased NA/Dopamine in hypothalamus
o Phentermine on its own does not have a huge effect on weight loss
o Phentermine + Topiramate
Together have additive effects
Topiramate anti-epileptic drug
Increases neuronal inhibition
Bupropion
o Inhibition of NA/Dopamine reuptake
o Stimulation of NA/Dopamine release
o Mechanism
Stimulation of inhibitory neurons in arcuate nucleus
Activation of POMC melanocortins and beta-endorphins
o Beta-endorphins
On its own stimulates food intake
Acts on mu opioid receptor
o Bupropion + Naltrexone
Given to combat the contrary effects of beta-endorphins (cleaved from
POMC)
Naltrexone is a mu opioid antagonist
Liraglutide
o GLP-1 agonist
Similar to exenatide
Increased insulin secretion, decreased glucagon secretion
o Treatment of Type 2 diabetes
o Effective in reducing body weight in non-diabetic obese people
Summary Tables
Week 8 GI Pharmacology
Learning Objectives
Understand the concept and mechanisms of disease of GI motility (constipation, diarrhoea,
nausea and vomiting), gastric acid secretion (GORD and gastric ulcer), pancreatitis and
diabetes mellitus
Understand mechanisms of action of pro-kinetic drugs, anti-spasmodic agents and anti-
emetics
Understand the mechanisms of gastric acid secretion and its pharmacological modification
Be familiar with pharmacological treatment of GORD and gastric ulcer
Be familiar with the pharmacological management of pancreatitis
GI Pharmacology
GI Motility issues
o Diarrhoea, constipation, nausea and vomiting
Gastric secretion issues
o Gastric ulcer and GORD
Pancreatitis
Pro-kinetic Agents
Promote coordinated contraction, motility and movements of material through GIT

Main class of drugs Dopamine Type 2 (D2) receptor antagonists
o E.g. Metoclopramide and Domperidone
D2 receptor antagonism
D2 receptors are inhibitory receptors on myenteric motor neurons
When stimulated, decrease myenteric motor neuron activity
Hence, antagonism leads to peristalsis
o Metoclopramide also
5-HT4 agonist
Vagal and central 5-HT3 antagonist
5-HT3 is an inhibitory receptor (allows for Cl- influx)
o Adverse effects stems from the fact they are D2 receptor antagonists
Metoclopramide
Extrapyramidal effects (Parkinsons-like disease)
o Due to chronic inhibition of D2 receptors
Galactorrhoea
o Dopamine is the physiological inhibitor of Prolactin
secretion
Domperidone
Galactorrhoea
Gynaecomastia
o Also explained by decreased inhibition of prolactin (D2
receptor antagonists)
Disrupted temperature control (hypothalamic centre)
Antimotility and Antispasmodic Agents
Primarily used to manage diarrhoea

o Diarrhoea associated with
Increased GI motility and secretions
Decreased absorption
Problem because of loss of water and electrolytes
o Treatments
Maintain fluids and electrolyte balance
Anti-microbials where appropriate
E.g. If diarrhoea is maintained by an infection
Antimotility and antispasmodic agents
mAChR antagonists
Opioids
Opioids
o E.g. Codeine, diphenoxylate, loperamide (Imodium, doesnt cross the BBB very well)
o Act as powerful inhibitors via mu opioid receptor (inhibitory receptor)
o Side effects
Constipation
Abdominal cramps
As it does cross the BBB a little bit
Drowsiness
Dizziness
Nausea, Vomiting and Anti-emetics
Is a defence mechanism getting rid of potentially dangerous things

When does it occur?
o Unwanted side-effects of many clinically used drugs
Cancer chemotherapy
Targets fast dividing cells and cells of the gut are fast dividing
Opioids
Via chemoreceptor trigger zone
General anaesthetics
Digoxin
o Motion sickness
o Early pregnancy (1st trimester)
80-90% of women
Mechanism unknown
o Disease states (migraine)
o Bacterial and viral infections
Reflex mechanisms
o Regulated centrally by vomiting centre and chemoreceptor trigger zone (CTZ) in the
medulla
o CTZ sensitive to chemical stimuli
Main site of action of many emetic and antiemetic drugs
BBB in CTZ is relatively permeable thus all the circulating
mediators/toxins reach/act directly on the CTZ
These potentially dangerous toxins cannot reach other areas of the
brain where they could do damage
Stimulatory receptors
NK1
D2
5-HT3
o Impulses from CTZ travel to the brain stems vomiting centre
Controls and integrates the visceral and somatic functions involved in
vomiting
Stimulatory receptors
mAChR
Anti-emetics
o Histamine type 1 (H1) antagonists Cyclizine and promethazine
Morning sickness
o Muscarinic antagonists Scopolamine
Motion sickness
o 5-HT3 antagonists Ondansetrone
Post-op, radiation, cytotoxic drugs, chemotherapy
o D2 antagonists Antipsychotics (chlorpromazine), metoclopramide, domperidone
GORD Gastro-oesophageal reflux disease
Family of conditions caused by gastro-

oesophageal reflux
Oesophageal injuries caused by GORD
o Oesophagitis
o Stricture
o Barretts oesophagus
o Adenocarcinoma
Treatment
o Lifestyle modifications
Stop smoking
Avoid large meals
Avoid certain food
Caffeinated
products,
peppermint, chocolate, spicy food, tomato-based products, alcohol,
fatty food, citrus, fruits and juices
o Weight loss
o Pharmacotherapy overlap with treatment of PUD
Regulation of Gastric Acid secretion
oStimulators
Gastrin
Released from G cells
CCK2 receptor on ECL
(enterochromaffine-like) cells
ECL cells release Histamine
Histamine acts on H2
receptors on parietal cells
o Increase intracellular
cAMP
Parietal cells secrete HCL
o cAMP activated
proton pump (H-K-
antiporter) which
also drives K-Cl
symporter
Direct vagal stimulation
ACh release at M3 receptors on parietal cells
Release HCl
o Inhibitors
Somatostatin
Prostaglandins
Pharmacological treatments of hypersecretion of gastric acid
o Antacids
They are just salts
Aluminium salts, calcium salts, magnesium salts, sodium
bicarbonate
Chemically neutralise stomach acid
Overuse metabolic alkalosis (due to it being basic)
Stay in stomach, so generally dont produce systemic side-effects
If patient has renal insufficiency
o Aluminium can cause osteoporosis, encephalopathy,
proximal myopathy
o H2 antagonists Cimetidine, ranitidine
Competitively inhibit H2 receptors
Inhibits histamine and gastrin stimulated acid secretion
Promotes healing of gastric and duodenal ulcers
Probably by continuous suppression of HCl secretion
o Proton pump inhibitors - Omeprazole
Irreversibly binds to H-K-ATPase pump
80-90% reduction in acid secretion
Secretion only returns upon enzyme replacement
o Hence new proteins must be synthetised hence, long-
lasting suppression 1-2 days
o Half-life 30mins to 2 hours (relatively short) compared to 1-
2 day effect due to irreversibility of the inhibition (new
proteins must be made before effect wears off)
Proton pump inhibitors are Pro-drugs
Side-effects
Abdominal pain, constipation, flatulence
Omeprazole is metabolized by CYP2C19
CYP2C19 is also involved in the activation of Clopidogrel
Thus, Omeprazole and Clopidogrel essentially compete for the
enzyme, which reduced the effectiveness of the anti-platelet drug,
Clopidogrel
o Prostaglandin analogues
Mucosa cytoprotective agents Misoprostol
Pro-drug
Mechanism of action
o Activate EP2,3 prostaglandin receptor on ECL cells
o Decreased cAMP production decreased histamine release
o Decrease gastric acid secretion from parietal cells
Additional effects
o Also activates EP2/EP4 receptors
o Increase cAMP
o Increase mucin and bicarbonate both protective
Contraindicated in pregnancy due to increased uterine contractions
o Prostaglandins can induce uterine contractions
Mucosa cytoprotective agents Sucralfate
Sucrose + aluminium compound
Creates crosslinked polymer in acid environment (stomach)
o Forms a physical barrier in stomach
Provides an extra lining protecting the mucosa
Prevents absorption of certain drugs, thus dosage
changes may be required
o Treatment of H. pylori infection
H. pylori infection has been implicated as a causative agent in the
production of gastric and duodenal ulcers a risk factor for gastric cancer
Eradication promotes rapid and long-term healing of ulcers
Using 1-2 week regime of triple therapy
o Proton pump inhibitor
o Amoxicillin antibacterial
o Metronidazole or clarithromycin antibacterial
Pancreatitis
Acute
o Causes severe pain with shock
o Associated with gallstones and/or alcoholism
o Treatment
Pain relief + replacement of plasma volume
Nutritional support may be valuable
Antibiotic prophylaxis
Prevents opportunistic infections in necrotic tissue
Chronic
o Progressive destruction of pancreas
o Treatment
Replacement of pancreatic enzymes
Digestive enzymes
Insulin
Milk-alkali Syndrome
Large doses of NaHCO3 and CaCO3 with milk or cream for the management of peptic ulcers
o Local antacid effects in stomach
o Systemic consequences
Mild hypercalcemia (due to diet) decrease in PTH secretions PTH
normally inhibits bicarbonate retention
Elevated calcium blocks aquaporin-2 channels in CDs of nephron
Less water retained
Polyuria polydipsia dehydration
If kidney is otherwise healthy, than this is what will probably happen
(not the steps below)
No PTH inhibition of bicarbonate retention more bicarbonate retention
metabolic alkalosis
Metabolic alkalosis decreased renal calcium excretion renal calcium
retention severe hypercalcemia renal vasoconstriction (via smooth
muscle) decreased GFR renal insufficiency
Further inhibition of PTH (via hypercalcemia) vicious cycle
o Symptoms
Hypercalcemia
Metabolic alkalosis
Renal insufficiency
Week 10 Pharmacology of Pain and
Analgesia
Learning Objectives
Describe the mechanism of action of opioid analgesics
Identify the primary side effects of opioid analgesics and link each to the mechanism of
action
Describe the mechanism of action of NSAIDs as analgesics
Describe the proposed mechanism(s) of action of paracetamol and contrast this with the
NSAIDs
Understand the two mechanisms of action of tramadol
Describe the mechanism of action of local anaesthetic
Outline the routes of administration of local anaesthetics and provide one advantage and
one disadvantage of each
Discuss the role of pH on the effectiveness of local anaesthetics
Describe the mechanism of action of tricyclic antidepressants as analgesic drugs in
neuropathic pain
Describe the mechanism of action of carbamazepine and gabapentin as analgesic agents in
neuropathic pain
Pharmacology of Pain
Pain
Molecular mechanisms of pain

o Tissue injury precedes pain
o As a result of tissue injury release of inflammatory and pain mediators
(inflammatory soup)
o These act on their corresponding receptors leading to changes in nerve ending
Characterised by increased intracellular calcium thus activation of cell
Synaptic control of pain (at dorsal horn - central)
o FON nociceptive afferent
o Inhibitory interneuron (containing for e.g. enkephalin)
o Descending projections from PAG (and other areas of brain)
o Dorsal root projection neuron (ascending through spinothalamic tract)
Pain is both a physical entity (via actual tissue damage leading to excitation of nociceptive
afferents) and an emotion
Pharmacological Management of acute pain
Peripherally acting analgesics

o NSAIDS
Centrally acting analgesics
o Paracetamol
o Weak opioids (Codeine)
o Tramadol
Adjuvants
o Corticosteroids
o Antidepressants
o Anticonvulsants
o Membrane stabilisers
o Local anaesthetics
Peripherally-acting Analgesics
Prostaglandins
o Prostaglandin Synthesis (PGE2 and PGI2)
All come from Arachidonic acid via activity of Cyclooxygenase (COX) enzyme
COX3
Only in brain
Inhibited by paracetamol
o Hence, explains why paracetamol is not a good anti-
inflammatory drug, but rather, a good antipyretic drug (anti-
fever) as it acts through hypothalamic centres
o Also good analgesic drug via PG inhibition (PGE2 and PGI2)
o Pain aspect of prostaglandins (PGE2 and PGI2-prostacyclin)

Vasodilatory effect (both? Im pretty sure its both)
Hyperalgesic effect (PGE2??)
NSAIDs (Non-steroidal Anti-inflammatory Drugs)
o Mechanism of action
Inhibition of COX-2
Hence, suppression of prostanoid (PGs + thromboxanes + prostacyclins)
synthesis
Anti-inflammatory mechanism
o Decreased PGE2 + PGI2 (prostacyclin) = reduced
vasodilation and oedema
Analgesic effect
o Decreased PG synthesis
Less peripheral sensitisation (see neuro week 10) to
inflammatory mediators (e.g. bradykinin, 5-HT)
Decreased PG mediated vasodilation (decreases
headache for e.g.)
Antipyretic effect
o ILK-1 releases PGs in CNS (hypothalamic preoptic area)
o PGs elevate hypothalamic set point for temperature
Fever
o NSAIDs inhibit this
o Side-effects
Stem from inhibition of COX-1
PGs cause afferent vasodilation in kidneys (increasing GFR)
NSAIDs cause afferent vasoconstriction (decreasing GFR) problem
for renal patients
o Selective COX-2 inhibitors (coxibs)
Were develop the mostly GI side-effects of NSAIDs (via COX-1 inhibition)
However, G disturbances may still occur
COX-2 though to play a role in healing of pre-existing ulcers
o Used for mild-moderate pain
Centrally-acting Analgesics
Opioids
o G-Protein Coupled Receptors
3 subclasses
Mu plays a role in analgesia (and mediation of side-effects)
Delta
Kappa
Negatively regulating i.e. inhibit the cell which they are on
Via negative coupling to adenylyl cyclase
o Hence, decreased cAMP production, thus decreased Ca
entry
Also via positive coupling to K channels
o Hence, activation leads to K efflux hyperpolarisation
Act pre- and post-synaptically inhibit pain signal transmission
Pre-synaptic inhibition (inhibition of neurotransmitter release)
o Via negative coupling to adenylyl cyclase decreased cAMP
decreased Ca decreased neurotransmitter release
Post-synaptically inhibition (inhibition of neuronal firing)
o Via activation of K channels K efflux hyperpolarisation
o Abuse potential via opioids inhibiting inhibitory mechanisms causing excitation

(disinhibition)
Disinhibition in Ventral Tegmental Area (VTA) hence, activation of mostly
dopaminergic pathways in the brain leading to euphoria
o Opioids effect on emotion
Opioids exert their effect on emotion via limbic mechanisms
If you give someone morphine for acute pain they know the pain is
still there, but it doesnt bother them any more
o Clinically used opioids
Morphine
Mu opioid receptor agonist
Moderate-severe pain
o Visceral or soft-tissue origin
Effects
o Analgesia primary effect
Effective for most acute and chronic pain (not
neuropathic)
Neuropathic pain is much less sensitive to
opioids
o Morphine-induces respiratory depression and suppression
of cough
Occurs with normal analgesic dose
Due to decreased sensitivity of arterial pCO2 at
respiratory centres
Thus, inhibition of respiratory rhythm generation
Most common cause of death in acute opioid
overdose
o Tolerance
In order to keep achieving same analgesic effects
dose must be increased
As we increase dose, we can easily hit threshold
which suppresses the respiratory centre
o Euphoria and sedation
o Nausea and vomiting (due to effect on CTZ)
o Reduced GI motility (due to inhibitory effect of mu receptor)
Increased tone, decreased motility
Pain due to gall stones SHOULD NOT BE TREATED
WITH OPIOIDS
Due to increased tone contraction of gall
bladder and constriction of biliary sphincter
(increased pressure in biliary tract) may
lead to rupturing of gall bladder
o Histamine release bronchoconstriction and hypotension
Codeine
Metabolised to morphine to exert analgesic effect
o Via demethylation via CYP2D6
Some people have a partial or complete loss of this
enzyme poor metabolisers
Autosomal recessive condition
Unable to metabolise codeine, hence no
analgesic effects
Antidepressants inhibit CYP2D6, hence if co-
administered, codeine lose efficacy
Tramadol
2 Mechanisms of Action
o Weak mu opioid agonist
1/6000th the affinity of morphine
o Also inhibits NA and 5-HT reuptake
Antidepressant effect similar to SSRIs
Analgesic effect via descending pathways more 5-
HT and NA in dorsal horn synapse inhibiting
transmission of pain
Pethidine (Meperidine)
Mu opioid receptor agonist
o Less potent than morphine
o Onset faster when orally administered vs IM or SC
Good for muscle spasms, but other than OB/GYN not really used
Hydromorphone
8 times more potent
Recommended for moderate-severe pain
o Often used for patients with opioid tolerance
Oxycodone
Equivalent to morphine
May be combined with non-opioid analgesics for moderate-severe
pain
o Pain associated with cancer is responsive to oxycodone
Strong abuse potential
o Anything highly active on mu opioid receptor has strong
abuse potential
Fentanyl
80 times more potent than morphine
o Used only for severe pain (as side effects also enhanced)
Adjuvants
Local anaesthetics
o Local anaesthesia loss of sensation in a limited region of the body
o Disrupt afferent impulses to spinal cord via inhibition of impulse generation or
propagation
o Physiologic changes attributed to their Na channel blocking action
Muscle paralysis
Suppression of reflexes
Reversible Na channel blockers the same ones used for anti-dysrhythmias
(e.g. Lignocaine)
Anti-dysthymic administration oral
Local anaesthetic administration inject locally
Hence, no Na influx hence no generation of APs
As they block APs can inhibit both sensory and motor functions
Although, sensory nerve fibres of small diameter and slow
conduction velocity (C and A-delta) are most susceptible to block
Na channels
Exist in 3 states
o Resting
o Open
o Refractory
Lignocaine
preferentially binds to
the refractory state of
the channel
This stabilises the state thus the channel cannot open for another
depolarisation
pH-dependence
Some LAs are weak bases hence at physiological pH exist in
charged (protonated) and uncharged (unprotonated) form
LAs block channel in charged form from the inside of the cell, hence
travel across (lipid bilayer) in uncharged form and then block in
charged form
At inflamed tissues pH is low (acidic)

o Hence, more LA in charged form (more H+ ions)
o Hence, cannot cross membrane
o Hence, less analgesic effect at inflamed tissues
Use-dependence
Some LAs are uncharged (e.g. Benzocaine)
The higher the rate of nerve stimulation the faster the block
o Due to higher likelihood that channel will be open
Hydrophobic pathway no use dependence
o Uncharged LAs pass through membrane and blocks Na even
if it is closed
o Does not depend on pH as it is uncharged
Hydrophilic use-dependent
o Charged LAs need the channel to be open to bind
o Hence, more likely channel is open (when high AP rate),
more likely charged LAs will bind
o Clinically
Treat or prevent acute pain locally
Problem of systemic toxicity if LA enters systemic circulation
Hypotension
Bradycardia
Respiratory depression
Chronic Pain Neuropathic Pain

Non-productive, maladaptive pain no use to us
Neuropathic/chronic pain is not due an actual injury
Clinical features Neuropathic pain
o Abnormal pain quality burning, cold, electric shock sensations
o Dysesthesias (non-painful abnormal sensations) tingling, pins and needles,
numbness, itching
o Sensory loss no touch, no pinprick perception
No sensation other than pain can occur
o Allodynia (painful response to usually not painful stimuli) e.g. wearing shirt over
sunburn (acute type)
In chronic allodynia type pain, there doesnt need to be that acute
injury/factor (sunburn, in this case) for there to be pain chronically
Central aspect to Neuropathic pain
o Pain initiated or caused by lesion or disease in CNS in the past (not present anymore)
E.g. Stroke pain, MS, spinal cord injury
Peripheral aspect to Neuropathic pain
o Pain initiated or caused by lesion or disease in PNS in the past (not present anymore)
PHN (post-herpetic neuralgia), trigeminal neuralgia (the fucked one),
diabetic neuropathy
Pathophysiology
o Changed expression of V-gated Na channels peripheral sensitisation
Leading to spontaneous activity in damaged afferents
o Sympathetic NS central sensitisation
Damaged afferents can express alpha-adrenoceptors (not present under
normal conditions) thus develop sensitivity to NA
Hence, stimuli that evoke SNS responses evoke severe pain
Sympathetically mediated pain
Treatment
o Poor responsiveness to NSAIDs and not very responsive to opioids
o Treatment depends on cause of lesion or disease and how long its been chronic
(chronicity)
The longer the pain is around, the more remodelling (plasticity and central
sensitisation), the more resistant to treatment
o Pharmacological options
Antidepressants SNRIs, TCAs
Anticonvulsants
Na channel blocker anticonvulsants
o E.g. Carbamazepine, Clonazepam, Sodium Valproate,
Phenytoin
o Dampen effect of increased Na channel expression
Neuropathic pain treatment drugs
Initially developed as anti-epileptic (not used any more)
Inhibit pre-synaptic V-gated Ca channels hence no
neurotransmitter release at dorsal horn (glutamate)
o Fairly common for patients with chronic neuropathic pain to get a combination of...
COX inhibitor (e.g. NSAIDs) decreased PG induced inflammation, hence
decreased peripheral sensitisation
SNRIs (e.g. Duloxetine) increased synaptic NA and serotonin via
descending inhibitory pathways (from periaqueductal gray for e.g.), hence
reduced nociceptive afferent transmission in ascending pathways
Serotonin modulates pro- and anti-nociceptive effects in
descending pathways from brainstem (PAG)
NA predominantly anti-nociceptive effect
Both need to be potentiated for analgesic effect
Anticonvulsants (e.g. Sodium Valporate) inhibit Na channels which may
have changed expression in chronic neuropathic pain
Opioids (e.g. Morphine) pre- (decreased cAMP, hence decreased Ca) and
post-synaptically (K channel activation, K influx) inhibits nociceptive
afferents via mu opioid receptors
Week 11 Pharmacology of Psychotic
Disorders
Learning Objectives
To understand the concept of psychotic disorders and be able to define schizophrenia and
bipolar disorder
To be familiar with the neuroanatomical systems and neurotransmitters underlying
psychotic disorders
To understand mechanisms of action of antipsychotics and anti-manic drugs
To understand the mechanisms of action of anticonvulsants in the treatment of mania
To understand the side-effects and possible complications that can emerge from the
administration of antipsychotics and anti-manic drugs
Schizophrenia
Neurodevelopmental disorder
Symptoms
Positive symptoms
o Hallucinations
Hearing voices from the outside
Very rarely good voices
Command to action hurt or kill someone or themselves
o Delusions (paranoid)
Firmly held beliefs the individual hold
E.g. external control, having thoughts inserted or withdrawn etc.
o Abnormal, disorganised behaviour
Stereotyped movements, disorientation and occasionally aggressive
o Thought disorder
Fragmented thinking, no logical procession of ideas
Words may make sense, but sentences have barely any meaning
Negative symptoms
o Withdrawal from social contacts social isolation
o Flattening of emotional responses
o Anhedonia inability to enjoy or experience pleasure
o These symptoms eventually lead to reluctance to perform everyday tasks (e.g.
properly dressing-up, looking after oneself)
Cognitive and other symptoms
o Deficits in cognitive functions
Not diminished IQ, no impairment in learning and memory
At least in beginning
Specific cognitive dysfunction, typical of abnormalities in prefrontal cortex
Selective attention
Executive memory
o Anxiety
o Guilt, depression, self-harm leading to suicide attempts in up to 50%
Aetiology
Genetic factors
o High heritability ~80%
o Inherited or de novo mutations
Environmental effects
o Prenatal factors virus, malnutrition, perinatal complications etc.
o Stress early childhood, adolescence
o Cannabis use
Interaction between genes and environment
Dopaminergic Pathways/Systems in Brain
Nigrostriatal system
o Substantia nigra Striatum (hence
name)
o Involved in Parkinsons disease
Mesolimbic system
o Ventral Tegmental Area (VTA)
Limbic system (amygdala,
hippocampus etc.)
Mesocortical pathway
o VTA Frontal cortex
Tubero-infundibular system
o Bottom of hypothalamus Pituitary
gland
o Dopamine released here, regulates
hormone secretion (inhibits
Prolactin secretion) from pituitary
Dopamines Role in Schizophrenia
Complex
o Positive symptoms (delusions, hallucinations etc.) overactivity in the mesolimbic
dopaminergic neurons (D2 receptors - inhibitory)
Target limbic regions (hippocampus, amygdala, nucleus accumbens)
o Negative symptoms (anhedonia, flattening affect, social isolation etc.) and Cognitive
symptoms (anxiety, depression etc.) decreased activity in the mesocortical
dopaminergic neurons (D1 receptors - excitatory)
Target frontal cortex
Pharmacotherapy
Antipsychotics
o All are D2 receptor antagonists
Hence, control Positive symptoms
o First-generation, typical or conventional antipsychotics

E.g. Chlorpromazine, haloperidol
(Disproportionally) High affinity for D2 receptor
o Second-generation, atypical antipsychotics
E.g. Clozapine, risperidone
Act on several other receptors besides D2
Low tendency to produce side-effects
o Side-effects
First-generation drugs (high D2 affinity)
Motor-disturbances looks like Parkinsons
o D2 receptors at Substantia Nigra inhibit striatum GP
external excited subthalamic inhibited GP internal
inhibited VA/VL excited movement (inhibited inhibitory
indirect pathway)
o D2 antagonists promote the indirect pathway, hence no
movement Parkinsons-like
o 2 types
Acute dystonia
Occurs when D2 receptors are blocked
acutely
Reversible
Involuntary movements, tremor, rigidity
Tardive dyskinesia
Develops slowly (many months)
Becomes irreversible
Chronically blocked D2 receptors signal
upregulation of dopamine receptors in
striatum
o These lead to hyperkinetic
involuntary movements of face,
limbs etc.
Endocrine problems (Prolactin)
o Via tubero-infundibular pathway
o Dopamine inhibits Prolactin secretion
o Hence, D2 antagonists increase secretion
o Hence, breast swelling, pain and lactation (men and women)
Anticholinergic symptoms
o Also bind to mAChR, hence anticholinergic effects
Second generation drugs (mixed effects on different receptors)
Metabolic syndrome weight gain, diabetes etc.
Anticholinergic symptoms
Other side-effects (for both)
Sedation antihistamine (H1) activity
Hypotension alpha-adrenoceptor block
Weight gain and increased risk of diabetes and CVD antagonistic
actions at H1, 5-HT and muscarinic receptors
Bipolar Disorder
Characterised by opposite mood states
o Balance of mania and depression varies greatly between individuals
o Mania
Hyper-aroused (euphoria or dysphoria)
Increased motor activity
Impaired judgment
o Depression
Depressed mood
Anhedonia
Impaired memory and concentration
Due to hyperactivity of neurons in brain and brain circuits (especially in manic phase)
o Parallels hyper-excitable state of brain in epilepsy
Pharmacology Mood stabilizers and others
Drugs may target

o Manic stage entirely
Lithium
Some antiepileptic drugs
o Depressive state
Antidepressants
Some atypical antipsychotics
Lithium interferes with intracellular signalling (IP3/DAG and GSK3)
o Mimics the role of Na in excitable tissues
Targets V-gated Na channels
Not pumped out by Na-K-ATPase
Accumulates inside cells partial loss of K (because of increasing
positive charge intracellularly) depolarisation
o Narrow therapeutic window
Clinically effective 0.5-1 mmol/L
Above 1.5 mmol/L toxic effects emerge
o 2 mechanisms of anti-manic action
Inhibition of inositol monophosphatase (IMPase) intracellular 2nd
messenger
Inositol monophosphatase hydrolyses inositol phosphate to free
inositol
Inhibition leads to block of phosphatidyl inositol (PI) pathway
o Hence, depletion of PI
o Hence, IP3 and DAG mediated signalling is depressed
Eventuating in Decreased intracellular Ca
Acute-effect of Li
Inhibition of glycogen synthase kinase 3 (GSK3) isoforms intracellular

enzyme/signalling molecule
GSK3 involved in apoptosis, cell death and other pathways
o Inhibitory enzyme, active all the time
Downstream of tyrosine kinase receptors (Trk, e.g. Insulin, NGF,
BDNF)
Inhibition
o Directly competing with Mg
o Indirectly stimulating PI signalling
Leads to changes in connectivity in neural networks
o Inhibition of GSK3 no inhibitory effect of GSK3
downstream neuroplastic changes, synaptic remodelling
hence, improved function
Chronic effect of Li
o Like antidepressants and antipsychotics, Li needs to be administered chronically to

have clinical efficacy hence, Lis anti-manic action isnt through IMPase inhibition
alone, GSK3 inhibition must also play a role
o Administration
Orally Li-carbonate salt
Excreted by kidney within 12 hours
o Na depletion can increase the reabsorption of Li at the
kidneys
o Diuretics also alter reabsorption of Li
Li accumulates slowly over 2 weeks before a steady state is reached
o Side-effects
Nausea, vomiting and diarrhoea
Renal effects
Polyuria, hence, polydipsia
o Via Li inhibitory effects on ADH
Na retention via increased aldosterone secretion
Prolonged treatment tubular damage
o Important to monitor renal function with chronic Li
treatment
Thyroid enlargement may be due to hypothyroidism (via Li)
Acute toxicity 3-5 mmol/L
Antiepileptic drugs
o E.g. Carbamazepine, Valproate, Lamotrigine
o Types aim to decrease hyper-excitability
Na channel blockers
Block production and propagation of APs
Potentiate activity of GABA (inhibitory neurotransmitter)
Antagonism of glutamate
Ca channel blockade
Inhibit pre-synaptic neurotransmitter release
o Valproate
*Used in neuropathic (chronic) pain, epilepsy and bipolar disorder treatment
Mechanism of action
Potentiates GABA activity
o Increases expression of enzyme making GABA (glutamate
decarboxylase)
Reduces protein kinase C (PKC) activity in manic patients
o Increased PKC associated with manic patients
Inhibits GSK3 similar to Li
o Leading to neuroplastic changes, synaptic remodelling,
hence, improved function
*Epilepsy, manic state bipolar, neuropathic pain all may be treated with similar drugs (e.g. Na
channel blockers, Ca channel blockers, increasing GABAergic tone etc.) hence, there must be
similar underlying mechanisms hyper-excitability of neurons*
Atypical antipsychotics D2 antagonists

o E.g. Olanzapine, risperidone, quetiapine
o Manic state is symptomatically similar to Positive symptoms of schizophrenia
Atypical antipsychotics primarily used to treat manic episodes
o Atypical drugs have a better side-effect profile (vs typical antipsychotics)
Do not produce extrapyramidal Parkinsons-like side-effects
o Used in combination with Li and/or Valproate
Olanzapine may be given in combination with fluoxetine
Fluoxetine SSRI, for management of depressed state
Week 12 Pharmacology of
Neurodegenerative Diseases, Epilepsy
and Drug Addiction
Learning Objectives
Parkinsons
o To understand the pathophysiology of Parkinsons disease
o Explain the different pharmacological ways to increase dopaminergic tone in PD
Alzheimers
o Outline the mechanisms of action of drugs used in the management of Alzheimers
disease
Epilepsy
o To understand how we can reduce excitability in epilepsy
o Outline the main classes of drugs used in the treatment of epilepsy and their
mechanisms of action
o Be familiar with the side effects and teratogenic effects of some anti-epileptic drugs
Addiction
o To understand the contribution of enhanced dopaminergic neurotransmission in
drug addiction
o To outline the drug classes and their main mechanism of action used in the
treatment of different aspects of addiction (detoxification, withdrawal treatment
and long-term management)
Parkinsons disease
Parkinsons
Progressive neurodegenerative disorder

o Effects control and regulation of movement
Dopamine deficiency in the substantia nigra
o Loss of dopaminergic cells
o Dorsal striatum does not receive sufficient dopamine
Probably accounts for motor symptoms
Symptoms
Hyperkinesia suppression of voluntary movement

o Due to increased muscle rigidity
Resting tremor
o Starting in hands (pill-rolling tremor)
Muscle rigidity
o Increased resistance to passive limb movement
Cognitive impairment
o Due to the ubiquitous nature of dopaminergic
neurotransmission in brain
Physiology of Dopaminergic Systems in Brain
Mesolimbic
o Ventral Tegmental Area (VTA)
Ventral Striatum
Overactivity Positive
symptoms of Schizophrenia
Mesocortical
o VTA Frontal Cortex
Underactivity Negative
symptoms of Schizophrenia
Nigrostriatal
o Substantia Nigra Dorsal Striatum
Responsible for motor side effects of antipsychotics (D2 antagonists)
D2 antagonists stimulate inhibitory indirect pathway no
movement
o Acutely (Acute dystonia)
Involuntary movements, muscle rigidity, tremor
o Chronically (Tardive dyskinesia) due to upregulation of D2
receptors
Hyperkinetic involuntary movements
o Physiology of Nigrostriatal DA system
2 pathways from SN (both begin in SN Pars Compacta)
Direct
o DA released from SN PC to D1r in Dorsal Striatum
Causes excitation
o GABA released from DS to SN PR
Causes inhibition
o No GABA released from SN PR to Thalamus
Allows excitation
o Glutamate may be released from Thalamus to Motor Cortex
Movement
Indirect
o DA released from SN PC to D2r in DS
Causes inhibition
o No GABA released from DS to Globus Pallidus
Allows excitation
o GABA released from Globus Pallidus to Subthalamic Nucleus
Causes inhibition
o No glutamate released from STN to SN PR
No excitation
o No GABA released from SN PR to Thalamus
Allows excitation
o Glutamate may be released from Thalamus to Motor Cortex
Movement
Pathophysiology of Parkinsons
Specific loss of dopaminergic cells in Substantia Nigra Pars Compacta

o Decreased stimulation of pro-kinetic direct pathway
Motor inhibition
o Decreased inhibition of anti-kinetic indirect pathway
Motor inhibition
Pharmacological Treatment of PD
Aim to increase DA transmission

Replace DA L-DOPA
o Dopamine synthesis
Tyrosine DOPA Dopamine NA A
Tyrosine DOPA via Tyrosine Hydroxylase
o Why cant we just give Dopamine?
Dopamine doesnt cross BBB
DA binds to DAr all around the body
Leads to side-effects mimicking Sympathetic Nervous System
activation
o We can give DOPA (precursor)
Penetrates BBB
Taken up by dopaminergic cells
If they still exist
In advanced PD it would be redundant to give DOPA as the few
remaining Dopaminergic cells cannot sufficiently supply DA
Also taken up by neurons of SNS in periphery
DOPA converted into DA and NA
o Hence, we need to prevent SNS neurons in periphery taking up DOPA and converting
it hence losing the efficacy of DOPA
We can do this by adding Carbidopa
Carbidopa DOPA decarboxylase inhibitor
o Does not cross BBB
o Taken up by SNS neurons in periphery
o Stops conversion of DOPA DA and hence NA
o DOPA + Carbidopa
Both taken up in periphery SNS
But no conversion of DOPA because of Carbidopa
Only DOPA crosses BBB
So there is conversion of DOPA in brain
Increasing Dopamine metabolism MAO-B inhibitors
o DA metabolised by 2 enzymes
MAO-B (Selegiline) DA to DOPAC
MAO-A metabolises NA and Serotonin preferentially
COMT (Tolcapone) DA to 3-MT
o Inhibiting these enzymes, increases DA concentration
DA receptor agonists (Bromocriptine)

o Act in Striatum (where D1 and D2r are found)
None of these treatments address underlying cause of PD (degeneration of dopaminergic

neurons)
Alzheimers Disease
Alzheimers Disease
Brain shrinkage and localised loss of neurons mainly in

the hippocampus and basal forebrain
o Neurodegenerative disease
Characterised by progressive memory loss
o Age-related dementia
Pathogenesis
2 main pathological features (biomarkers)

o Extracellular Amyloid plaques
Amorphous extracellular deposits of
Beta-amyloid protein
o Intracellular Neurofibrillary tangles
Filaments of a phosphorylated form
of Tau (microtubule-associated
protein)
Features responsible for clinical symptoms
o Loss of cholinergic neurons
In hippocampus and Frontal cortex
o Loss of cholinergic transmission or low levels
of ACh is associated with learning and memory impairments
Anticholinergics impair learning and memory
Pharmacological Treatment
Do not treat underlying cause of AD rather an attempt to maintain functional cognition

o By boosting cholinergic system (cholinergic drugs) or
o NMDA antagonists inhibiting the excitotoxicity (loss of neurons via huge influx of
Ca) caused by NMDA mediated stimulus
Cholinergic drugs Cholinesterase inhibitors (AChE inhibitors)
o AChE metabolises ACh
o Hence, AChE inhibitors boost ACh levels and hence, cholinergic
transmission/signalling
To compensate for the loss of cholinergic transmission
o Slight improvement of cognitive function
o E.g.
Donepezil, Rivastigmine, Galantamine, Tacrine
NMDA antagonists
o E.g. Memantine weak antagonist
Non-competitive
o Mechanism
Interacts with Mg binding site
Prevents excess excitation whilst sparing normal function
Acts like a modulator
Epilepsy
Epilepsy
Symptom more than a disorder

Characterised by imbalance between excitatory (glutamate) and inhibitory (GABA) circuits
within brain
o Therapeutic aim 1 (target seizure generation) essentially too much excitation, so
need to decrease
Increase GABA activity successful
Decrease Glutamate activity not as successful
o Therapeutic aim 2 (target spread of APs) APs spread out from the focus creating a
synchronous wave of depolarisation
Pharmacological Treatment
3 main mechanisms of Antiepileptics

o Enhancement of GABA activity
o Inhibition of Na channel function
o Inhibition of Ca channel function
Enhancement of GABA transmission
o Synaptic biochemistry of GABA
GABA-B receptor
GPCR too slow for pharmacological intervention
GABA-A receptor
LGIC Cl influx
o Hyperpolarises cell
GABA metabolism
GABA-transaminase metabolises GABA
GABA reuptake
GABA transporter (GAT-1) decreases synaptic availability of GABA
o Hence can target metabolism, GABA-A, GAT-1
o GABA-A channel modulators
o Barbiturates
GABA-A channel allosteric modulators
Facilitate effect of GABA
Prolongs duration of open-time of channel increased Cl influx
hyperpolarisation
o Benzodiazepines
GABA-A channel allosteric modulators
Identical action to barbiturates
Good for acute seizures
o Valproate absence seizures
Multiple mechanisms of action effectively increases inhibitory tone within
NS (potentiates GABA)
Inhibits GABA-T primary mechanism
Potentiates GABA activity post-synaptically
Inhibitory effects on Na and T-type Ca channels
o Gabapentin
Augments GABA release from pre-synaptic terminal
Enhances GABA release
Inhibition of Na channel function

o Some anti-seizure drugs prolong inactivation of Na channels reducing ability of
neurons to fire at high frequencies
o Carbamazepine
Use-dependent block of Na channels
Can also be used in neuropathic pain and bipolar disorder
o Phenytoin 1
Use-dependent modulator of Na channels
Increases time for recovery of Na channels reduction in frequency
of firing
Inhibition of T-type Ca channel function absence seizures
o Some anti-seizure drugs reduce flow of Ca through T-type Ca channels
T-type Ca channels influence thalamic rhythms which, when abnormal,
contribute to absence seizures
So particularly effective against absence seizures
o E.g.
Ethosuximide
Valproate
Side-effects of Antiepileptics
Teratogenic effects (in about 6%)

o Spina bifida
o Cleft palate
o Congenital heart defects
o Microcephaly
o Management of epilepsy during pregnancy
Valproate higher incidence of malformations, particularly if used in first
trimester
Gum hyperplasia
o Most common manifestation of Phenytoin toxicity
Drug Addiction
Drug Addiction
A chronically relapsing disorder

o Compulsion to seek and take drug
o Loss of control in limiting intake
o Emergence of negative emotional state when access to drug is prevented
Dysphoria, anxiety, depression, irritability
Withdrawal
Brain Circuits Involved
There are neuronal circuits underlying natural reward

o Brain dopaminergic pathway Mesocorticolimbic pathway
All natural rewards, activate this system
Essentially, natural rewards slightly activate this pathway, whereas chemical (drug) rewards
hyper-activate it (huge release in dopaminergic tone)
Genetic and Environmental Effects
Genetic factors account for 40-60% of risk

Environmental factors (like poverty, crime,
delinquency) also have an effect
Treatments
Withdrawals
o Can be managed by anxiolytic drugs
Alcoholism
o Disulfiram
Inhibits alcohol dehydrogenase (ALDH)
Increased acetaldehyde after drinking feel very very bad
Works via classical conditioning
o Naltrexone
Mu opioid antagonist
Nicotine
o Nicotine replacement
Maintains blood nicotine level
o Bupropion (antidepressant)
Opiate withdrawal
o Methadone
Opioid agonist
Opiate addiction
o Methadone
o Naltrexone

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Pharmacology MD2012

Week 1 Pharmacology ............................................................................................................................ 8

ACh produced by neurons by acetylation of choline and acetyl-coA

Nicotinic receptors nAChR

Mimic action of ACh at mAChR or mAChR (agonists)

Two main receptor classes alpha and beta

Activation or blockage of receptors

Due to insufficient blood perfusion, cardiac muscle uses anaerobic respiration

Stable (angina due to increase in demand)

Principal Therapeutic Goals in Angina

Normal Endothelial Cell Function

Endothelial cells themselves cannot contract/relax, however, neighbouring smooth muscle

Treating Myocardial Infarctions

cAMP in cardiomyocytes causes contraction (opens Calcium channels, hence contraction)

Names all end in pril

First line in HT and HF

ANG II receptor (AT1) Antagonists (AKA Sartans)

All end in sartan

Inhibit binding of ANG II to AT1 receptors (AT1 receptor antagonists)

Decrease PVR via vasodilation mediated through alpha1-antagonism

Beta-blockers (Beta 1 selective)

Angina, HT, some helpful in HF, arrhythmias, post-MI

Inhibit sympathetic activity at Beta 1 receptors in heart

Hypotension, fatigue, bronchoconstriction (see wk 2 pharm notes), cold fingers/toes (due to

Poorly controlled asthma

Other drugs that lower HR, BP

Mixed Alpha and Beta-adrenoceptor Antagonists

Really only one in use Carvedilol

Hypertension, HF, angina

Blocks both, Beta-1, 2 and Alpha-1 adrenoceptors

Calcium Channel Blockers

Inhibit influx of Calcium via L-type (long) VGCCs

Systolic HF, hypotension

Other drugs that lower BP, HR

Clonidine, methyldopa, moxonidine

Work in brainstem to decrease sympathetic outflow

Dizziness, sedation, depression, erectile dysfunction, dry mouth, hypotension

Bradycardia, Coronary artery disease (CAD), depression, diabetes, HF

Other CNS depressants

Endothelin Receptor Antagonists

Pulmonary arterial HT only

Endothelin-1 (ET-1) receptor antagonists

Reduced hemoglobin, flushing, oedema, headache

Approaches to drug treatment

Aim to improve CO, minimize congestion

Inhibits aldosterones DCT action (reabsorption of Na, secretion of K)

Sympathomimetics (not used much any more)

HF secondary to MI, cardiac stress testing

Mimic actions of SNS

Digoxin/Digitalis (Cardiac glycoside) see week 4

Heart failure second line to ACE inhibitors

Normally, there is a Ca-Na antiporter in cardiomyocytes

Adverse Effects (see GLS apparently, is it a negative dromotropic drug??)

Narrow therapeutic index

Other drugs that slow cardiac contraction???

Sinus Node Inhibitors

Decrease HR via block of I (funny) pacemaker currents in SA node thus decreasing HR

Increases Alzheimers risk

Drug treatment for HT

Exam type question:

Thiazide Na-Cl co-porter in the DCT of nephron

Dihydropyridine L-type Ca channels in smooth muscle cells on vasculature

Dysrhythmias and their treatment

Genetic Mutations and Polymorphisms