Download Drugs acting on sympathetic α and β receptors Agonists - Di-Et-Tri

Pharmacodynamic interactions
- ACE inhibitors and K+
- Spironolactone and K+
- MAO inhibitors and tyramine
- Vitamin K and coumarines
- Combination of alcohol and CNS drugs
Specific diets and eating habits:
Problems (or “surprises”) may be expected with:
. Supplements containing much calcium, magnesium, iron or zinc
. Vitamin-preparations
. Fibers
. Herbs
. Extensive weight loss
Drug-induced nutrient deficiencies = Effects of drugs on nutrients
Effects on taste:
* ACE inhibitors
* Allopurinol
* Methotrexate
* Metronidazol
* Penicillamine
Effects on appetite / satiety / hunger
* Digoxin and fluoxetin inhibit appetite
* Stimulation of appetite: most SSRI’s, TCA’s, Valproate, Cannabis
Drug effects on nutrient absorption?
; Laxantives (some)
; (old) cholesterol lowering drugs (colestyramine)
; Orlistat
Take care with already diminished uptake (mal-absorption syndrome) and deficient diets
Brief summary: Do food and diet interact with drugs? Yes, and possibly more often than we think.
However, this will not be noticed or be relevant.., but how much do we miss? Many mechanisms are
known, but some are more common. Predictions are still difficult to make. Interactions are not very
specific for certain therapeutic groups. Relatively important are antibiotics, HIV protease-inhibitors,
bisphosphonates, immunosuppressants and certain cytotoxic drugs. Don’t forget the food
supplements and herbal preparations, and be aware for surprises
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Lecture 7 Pharmacology of the autonomous nervous system
Nervous system:
• Important physiological regulatory system
• Target for many drugs and other bio-active compounds
• Functionally and anatomically divided in the sympathetic and parasympathetic nervous system
Neurons or nerve cells:
- Receive stimuli and transmit action potentials
- Organization: • Cell body or soma
• Dendrites: Input
• Axons: Output
Neuroglia or glial cells:
- Support and protect neurons
Types of neurons
Functional classification
- Sensory or afferent: action potentials towards CNS
- Motor or efferent: action potentials away from CNS
- Interneurons or association neurons: within CNS from one
neuron to another
Structural classification
> Multipolar (a)
> Bipolar (b)
> Unipolar (c)
Cells produce electrical signals called action potentials
Transfer of information from one part of body to another
Electrical properties result from ionic concentration differences across plasma membrane and
permeability of membrane
Action potential
Series of permeability changes when a local potential causes
depolarization of membrane
Phases  Depolarization (more positive)
 Repolarization (more negative)
= All-or-none principle
Refractory period
Sensitivity of area to further stimulation decreases for a time
Parts: - Absolute
• Complete insensitivity exists to another stimulus
• From beginning of action potential until near end of
repolarization
- Relative
• A stronger-than-threshold stimulus can initiate another
action potential
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The synapse
Junction between two cells
Site where action potentials in one cell cause
action potentials in another cell
* Components:
Presynaptic terminal
Synaptic cleft
Postsynaptic membrane
* Neurotransmitters released by action
potentials in presynaptic cleft
Synaptic vesicles
Diffusion
Postsynaptic membrane
* Neurotransmitter removal
Neurotransmitter degradation
MAO can be inhibited by antidepressant drugs
The autonomic nervous system
Subdivisions
- Sympathetic nervous system
- Parasympathetic nervous system
Indirect innervation (>2 neurons):
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~ Sympathetic nervous system
- Fight or Flight
- Produces tachycardia (increased heart rate)
- Raises blood pressure
- Dilates the pupils
- Dilates the trachea and bronchi
- Stimulates the conversion of liver glycogen into glucose
- Shunts blood away from the skin and viscera to the skeletal muscles, brain, and heart
- Inhibits peristalsis in the gastrointestinal (GI) tract
- Inhibits contraction of the bladder and rectum
~ Parasympathetic nervous system
- Leads to bradycardia (lowering blood frequency)
- Lowering of blood pressure
- Constriction of the pupils
- Increased blood flow to the skin and viscera
- Peristalsis of the GI tract
Effect of the ANS
* Antagonistic control
. Structures served by both sympathetic and parasympathetic nerves
. The effects are usually opposite or antagonistic
. Most structures that receive parasympathetic innervation also receive sympathetic innervation
. Most internal organs, salivary glands, tear glands, and intrinsic eye muscles
*Tonic control
. Some structures are only served by the sympathetic system (adrenal glands)
. Skin: sweat glands, errector pili
. Most vasoconstrictors (vascular smooth muscle)
* Drugs acting on sympathetic α and β receptors
Agonists
Antagonists
* Drugs acting on Muscarinic receptors
(“cholinergic”) Agonists
(“cholinergic”) Antagonists
*Indirectly acting drugs
Neurotransmitters
□ All preganglionic neurons, both sympathetic and parasympathetic
• Release acetylcholine (Ach) onto nicotinic (ion channels) Ach receptors on all the postganglionic
dendrites
• Always excitatory
□ Sympathetic postganglionic neuron
• Release Norepinephrine (noradrenaline)
• Maybe excitatory or inhibitory depending on the receptor subtype and the cell type
□ Parasympathetic postganglionic neuron
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• Release Ach
• Usually on muscarinic (GPCR) receptors, effect is usually excitatory
* Drugs acting on sympathetic α and β receptors
Agonists
Antagonists
* Drugs acting on Muscarinic receptors
(“cholinergic”) Agonists
(“cholinergic”) Antagonists
*Indirectly acting drugs
Sympathetic nervous system
Beta1 – receptors: increases heart frequency and contractivity
Agonists? Yes, but limited [special situations] use:
Dobutamide: β1 – agonist: positive inotropic action
For acute situations: decompensation, shock etc.
Beta1 – receptors: block the beta receptors
Antagonists? Yes!
Beta-blockers (selective β1 –blockers and [less favourable] non-selective β1/β2) are first choice in
• Angina pectoris
• Hypertension
• Others (including tremors [β1/β2])
(Non-selective β1/β2 blockers may cause bronchoconstriction)
Examples:
Selective: acebutolol, atenolol, betaxolol, bisoprolol, metoprolol etc.
Non-selective: pindolol, propranolol, sotalol etc.
Beta1 – antagonists: main effects
Decrease of blood pressure
Decrease of cardiac output (and decreased AVconduction)
Decreased peripheral circulation
Beta2 – receptors: dilation of bronchi
Agonists? Yes!
Main indication: symptomatic relief of asthma = reversible bronchoconstriction
For example: Clenbuterol Side effect: Increase of muscle formation and – strength + Decrease of
fat tissue (in animals) but… tremor….
Beta2 – receptors
Antagonists? NO! (at least not specifically intended…)
Beta3 – receptors
β3-agonists are very effective thermogenic antiobesity and insulin-sensitising agents in rodents
Lots of effort has been put in search for agonists active in humans since 1990
Problems with receptor selectivity and species differences in types of fat tissue prevented a breakthrough
With discovery of brown fat in humans of adult age this may change…
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Alfa1 – receptors: in wall of small arteria
Agonists? Yes, but limited use
• Used for local effect as anti-congestive in the nose
• I.e. vasoconstriction of your nose: Xylometazolin (OtrivinR) , Oxymetazolin (NasivinR)
Alfa1 – receptors
Antagonists? Yes, but again limited
•To prevent urinary retention for example in benign prostate hypertrophy: tamsulosin, alfuzosin etc.
•To produce lowering of blood pressure via peripheral vasodilatation: effective but not first choice
(e.g. prazosin)
• For Raynaud’s syndrome (vasoconstriction due to cold exposure) (limited cases)
Alfa2 – receptors
Agonists? Yes, but limited
Clonidine causes drop in blood pressure via central β2 receptors – Clinically not first choice therapy
Alfa2 – receptors
Antagonists? Not in clinical use, but as “food” supplement (yohimbine)!
Indirectly acting sympathomimetics (simulate the sympathetic actions)
 More NE in synapse
Ephedrine: alkaloid from Ephedra, in ma huang. In many (illegal) food supplements (weight loss etc.)
Amphetamine: CNS stimulant. In the past its analogue fenfluramine (PonderalR) was used as appetite
suppressant. Also used as sports doping: highly potent, dangerous and addictive physical and mental
stimulants
Tyramine: in fermented food products (see food-drug interactions)
Methylphenidate: RitalinR (known ADHD drug) used by students during exams
Parasympathetic nervous system
Cholinergic Pharmacology
* Muscarinergic agonists (parasympathomimetics)
Use? Limited, only for glaucoma (obstruction of fluid from the eyes):
Pilocarpine (and bethanechol)
Systemic : side-effects [SLUD] = Salivation Lacrimation Urination Defectation
* Muscarinergic antagonists (parasympatholytics)
Mostly non-selective for M-subtypes
Atropine, Ipratropium, Scopolamine
Atropine: Increases heart rate, Decreases secretion, Relaxation of smooth muscle – bronchi, urinary bladder,
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GI tract (also : butylscopolamine), Dilation of pupil, Relaxes ciliary muscle – focus far vision
Adverse effects: Dry mouth, constipation, blurred vision, increased intraocular pressure, urinary retention,
tachycardia, asthma – drying of secretions
Scopolamine: Produces sedation, Suppresses emesis and motion sickness
* Neuromuscular blocking drugs
Most of them cause a reversible non-depolarizing neuromuscular blockade
Competitive inhibition of ACh receptors at motoric endplate
Prototype : Curare
Tubocurarine (from curare)
Now : Suxamethonium, Pancuronium, Mivacurium
All quarternary amonium compounds (  kinetics !)
Mainly used for muscle relaxation during operations and other medical interventions
* Cholinesterase inhibitors
Enhance effects of Ach
Reversible, for example in Myasthenia gravis (autoimmune disorder in which nicotinic M receptors are
reduced at neuromuscular junction)
Irreversible: in insecticides and certain nerve gasses. Medical use limited (glaucoma)
Used in dementia - - > modest improvement of some symptoms (memory and cognition)
Cholinergic crisis
= Overdose with cholinesterase inhibitors
Increased bronchial secretions, Respiratory failure
Atropine may be helpful
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Lecture 8 Cardiovascular Pharmacology
Cardiac output = Volume of blood pumped by each ventricle each minute
CO=Heart Rate X Stroke Volume
At rest: 4.5-5 l/min; During exercise: 20-25 l/min
Regulation of Arterial Pressure
Arterial pressure = peripheral resistance (passive) x cardiac output
Arterial pressure is determined by:
1. The autonomic nervous system (fast)
2. The renin-angiotensin system (hours or days)
3. The kidneys (days or weeks)
preload: indication of the stretching of the cardiac muscle prior to contraction. Determined by blood
volume/venous filling and degree of venoconstriction
afterload: The "load" that the heart must eject blood against. Afterload is related to ventricular wall
stress and proportional to aortic pressure. Increases in case of constriction or arteria (and arterioles)
cardiac muscle:
• pacemaker activity
• slow Ca influx initiates action potentials in SA
and AV nodes
• long action potential and refractory period
• influx of Ca during plateau
Arrhythmias (dysrhythmias), main forms:
Tachyarrhythmias: increases heart rate
- atrial fibrillation and SVT
- ventricular tachyarrhythmias and ventricular fibrillation
Bradyarrhythmias:
- heart block (different types)
- asystolic arrest (no heart function --> death)
--> severe
Main causes:
• Delayed after-depolarisation (→ ectopic beats)
• Re-entry
• Ectopic pacemaker activity
• Heart Block
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Generation of a re-entrant rhythm by a damaged area of
myocardium. The damaged area (brown) conducts in one
direction only. This disturbs the normal pattern of
conduction and permits continuous circulation of the
impulse to occur.
Antiarrhytmic (antidysrhythmic) drugs : different classes,
different actions
Class Compounds
Ia
disopyramide, kinidine, procainamide
Ib
fenytoïne, lidocaïne, (aprindine)
Ic
flecaïnide, propafenon
II
β–blockers
III
amiodarone, ibutilide, sotalol
IV
diltiazem, verapamil
 medical treatment in persistent arrhythmias is risky and success rate is often disappointing
Calcium channel blockers
Prevent calcium from entering cells (L-type channels)
Used for hypertension, angina, cardiac dysrhythmias (not all !)
- delay conduction in SA- and AV-node
- cause vasodilatation (coronary and systemically), leading to BP↓
- some: negative inotropic effect.
Example : Verapamil
Blocks calcium channels in the blood vessels and heart
Given (orally or IV) for arrhythmias
Ind: certain arrhythmias, angina pectoris, hypertension
Ischemic heart diseases
Result of inadequate blood supply to the heart muscles
Most commonly due to atherosclerosis
Secondary risk factors: Obesity, Diabetes, Excess alcohol, Lack of exercise, Oral contraceptives,
Personality type, Renal disease
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Angina pectoris
Classification
Stable angina = most common
- frequently due to atherosclerotic plaques
Unstable angina - due to thrombus formation and rupture
- 10-15% risk of death/MI
Variant angina – uncommon
(Prinzmetal’s) - attacks occur at rest
Drug treatment:
Goals – prevent pain, MI and death
Organic nitrates, Ca-antagonists and beta-blockers
Management of angina, nitrates
Nitroglycerin
. Organic nitrate
. Acts on vascular smooth muscle to promote vasodilation
. Primarily works on veins
. Modest dilation arterioles
. Decreases oxygen demand by decreasing venous return (reduced preload) – stable angina
Routes of administration
□ Oral, sublingual, IV, buccal, transdermal
□ Crosses membranes easily
□ Adverse effects – headache, tachycardia, hypotension
□ Do not combine with other drugs causing vasodilation (Viagra) or hypotensive drugs
Tolerance can occur – give lowest dose possible
Drug-free period every day
Long-acting preparations vs preparations for acute attack
Beta-blockers in angina pectoris:
- Reduce myocardial oxygen demand
- Cardioselective beta-blockers are most effective
- Minor side-effects
Calcium antagonists in angina pectoris:
- Used in prophylaxis
- Reduce afterload and therefore myocardial oxygen demand
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Myocardial infarction
Management of MI
* Defibrillators
* Pacing
* Thrombolytic therapy (streptokinase, urokinase, tenecteplase etc.)
Heart failure
Major causes – hypertension, myocardial infarction
Inadequate tissue perfusion from a failing pump, volume overload
Clinical signs:
; Oedema (fluid retention)
; Dyspnoea (breathlessness)
; Cyanosed lips and face
The vicious cycle: Cardiac dilation  Increased sympathetic tone  Water retention and increased
blood volume …..
Classification of severity:
I – no limitation of physical activity
II – slight limitation
III – marked limitation
IV – symptoms occur at rest
Non drug therapy:
- Sodium limitation
- Avoid large amounts of fluid
- Lose weight if indicated
- Avoid alcohol
- Mild activity
Drugs for Heart Failure
> ACE inhibitors: inhibit renin-angiotensinaldosteron system
> Diuretics: increase natriuresis
> Beta blockers: inhibit sympathetic nervous system
> Digoxin: increase cardiac contraction force
> Spironolactone: inhibit ADH
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Digoxin
* Cardiac glycoside – improves cardiac performance – positive inotropic
* Narrow therapeutic range
* Competes with potassium for binding – when potassium is low, digoxin effects become stronger
* Once used frequently, but now rapidly decreasing
Effects of digoxin:
Increases cardiac output + Decreased sympathetic tone + Increased urine output + Decreased renin
release + Does not prolong life + Effects electrical activity –> decreased conduction thru AV node,
decreases automaticity of SA node
Adverse effects:
DYSRHYTHMIAS, TOXICITY (very narrow therapeutic index) –> hypokalaemia makes it easier for
toxicity to occur, GI – disturbances, Fatigue, Visual disturbances
Drugs acting on the Renin-Angiotensin System
. Angiotensin-converting enzyme (ACE) inhibitors
. Angiotensin II receptor blockers (ARBs)
. Primary indications – hypertension, heart failure, myocardial infarction, diabetic nephropathy
How does it work?
Angiotensin I, II, III
Most potent – angiotensin II
Produces profound vasoconstriction and stimulates release of aldosterone and may also cause
pathologic structural changes in the heart and blood vessels (especially bad after an MI)
Captopril
- First ACE inhibitor
- Given po
- Inhibits ACE
- Reduction in blood volume, vasodilation, prevent remodelling
Adverse effects: Cough, first-dose hypotension, hyperkalaemia, renal failure, foetal injury,
angioedema, rash, neutropenia, impaired taste
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Angiotensin II Receptor blockers
• Block actions of angiotensin II
• Losartan (Cozaar) – does not cause angioedema or cough
• Approved for hypertension only
• Doesn’t appear to cause hyperkalaemia
• Contraindicated in pregnancy
Hypertension:
Systolic BP ≥ 140 mm Hg or Diastolic BP ≥ 90 mm Hg
“cut-off” not absolute ! (risk already increasing at mild elevation)
Risk groups BP ≥ 130/80 mmHg
Consequences
* Heart disease, kidney disease, blindness, stroke
* Virtually no symptoms
* Goal of treatment – systolic < 140 and diastolic < 90
Drugs for hypertension:
 Should include lifestyle modification and drug therapy
- Primary (essential)
- Secondary
Treatment is usually life-long and non-compliance is a problem
Management – lifestyle:
Weight loss, Sodium restriction, Alcohol restriction, Exercise, Smoking cessation, Maintenance of
potassium and calcium intake
Initial Drug Selection
- With no other conditions – diuretic or beta blocker
- > 60 years: diuretic (thiazide) [Ca-antagonist]
- Diabetes II: ACE-inhibitor [beta-blocker, thiazide diuretic]
- Angina pectoris: beta-blocker [Ca-antagonist]
- With African genetic background: thiazide [Ca-antagonist]
~ Combination therapy: Lower doses of each drug, fewer side effects, better compliance
Beta – blockers
- First-line therapy (use declining in hypertension?)
- Mechanism of action:
Reduce cardiac output;
Inhibit renin release, AT-II and aldosterone production, and lower peripheral resistance
May decrease adrenergic outflow from the CNS.
Diuretics
. Increase output of urine
. Indications are primarily hypertension and mobilization of oedematous fluid as in, kidney problems,
heart failure, cirrhosis
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Mechanisms of action
* Blocking reabsorption of sodium and chloride
* Then water will stay in the nephron as well
* Diuretics that work on the earlier nephron – have greatest effect – since able to block more Na and
Cl reabsorption
Loop diuretics
° Furosemide – site of action loop of Henle (most effective)
° Blocks reabsorption at ascending limb of loop of Henle (20% Na and Cl)
° Orally, IV, IM
Thiazide Diuretics
° Effects are similar to loop diuretics but diuresis is lower
° Hydrochlorothiazide
° Early distal convoluted tubule (so later when there is less Na and Cl than loop diuretics)
° Must have adequate kidney function for these drugs to work
Potassium-sparing diuretics
° May be used in combo with loop diuretics or thiazides due to potassium-sparing effects
° Produce little diuresis
° Amiloride, spironolactone, triamterene
Osmotic diuretics
° Mannitol – inhibits passive reabsorption of water
° Uses include – prevent renal failure, reduction of intracranial pressure, reduction of intraocular
pressure
° Only given IV – can crystallize – give with filter needle, in-line filter
Ca-antagonists (….continued)
- Dihydropyridines, for example nifedipine – act mainly on vascular smooth muscle
- Blocks calcium channels in vascular smooth muscle – vasodilation
- Given for angina, hypertension
- Adverse effects: dizziness, reflex tachycardia
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Summary hypertension
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Lecture 9 Pharmacology of weight management and complications of obesity
Metabolic syndrome:
□ Abdominal obesity
□ Hyperinsulinemia
□ High fasting plasma glucose
□ Impaired glucose tolerance
□ Hypertriglyceridemia
□ Low HDL-cholesterol
□ Hypertension
Overweight: what are the options?
• Behavioural / lifestyle
• Specific dietary products
• Medical
* Bariatric surgery
 most effective
* Drugs
To reduce energy intake + To reduce adipose tissue or risks arising from it
Specific dietary strategies and products
•Different diets come and go: Atkins, Southbeach, Sonja Bakker...
•Become aware of eating habits is often effective in itself
•There is evidence that proteins are more satiating than other macronutrients
•Some foods are associated with lower body mass and/or increased satiation: Low GI products; fruits
and vegetables, high fibre content...
People are longing for easier alternatives:
Nutritional (incl. supplements and herbal drugs) vs. Pharmaceutical
Supplements can be dangerous: For example Dintrophenol (DNP) = toxic (and alikes), Beta-agonists,
Amfetamine-likes, including methylphenidate (RitalinR)
Medical options: Bariatric surgery
* Gastric bypass
* Gastric bandage
• Effective but not the “ideal solution”
•Only indicated in very obese or patients at risk - - > long-term weight loss, improved lifestyle
•Not to be confused with liposuction
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Pharmacological strategies to manage body weight: a battle against the most powerful instincts
Expensive
€High prevalence
€Clear unmet medical and social need
€Not much competition so far
€Successful drug will become blockbuster
Pharmacological targets in obesity
- Decrease food consumption
- Reduce energy absorption from GI tract
- Reduce body fat by stimulating energy expenditure or inhibiting energy
- Reduce inflammatory status
- Modulate body fat distribution, energy fluxes or mimic physical exercise
- Minimize pathophysiological complications
What’s available at the moment?
•EU: only Orlistat (as XenicalR, 120 mg [prescription] or AlliR, 60 mg OTC)
•Newcomers: Lorcaserin, Phentermine+Topiramate and Naltrexone+Bupropione
Some pharmacological targets under development:
GI tract: reducing energy absorption or stimulation of satiation
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Interfering with the action of satiety
and adipose tissue hormones
GLP-1 agonists (i.e. liraglutide,
exenatide)  leads to weight loss (in
overweight/obese patients).
Beneficial effects on systolic and
diastolic blood pressure, plasma
concentrations of cholesterol, and
glycaemic control. Side-effects:
nausea, diarrhoea, and vomiting (no
hypoglycaemia).
GLP: normally secreted by GI tract cells, effect on insulin (anti-diabetic) + signals to brain
Hypothalamic targets
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Regulation of feeding behaviour at different levels
Wanting: anticipatory/approach phase of the feeding
important mediator: Dopamine
Liking: hedonic aspects of the consummatory act
important mediators : Endocannabinoids and opioids
Effects of CB1 stimulation: non homeostatic overconsumption and fat storage
Second generation CB1 blockers
•Different kinetics: relatively lower brain concentrations and more peripheral action
•Different dynamics: no inverse agonists like rimonabant, but neutral antagonists or partial agonists
Reduction of risks without losing weight
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Physical exercise is beneficial
> Improves symptoms of metabolic syndrome independently from weight loss
> Improves cardiometabolic fitness
> Improves muscle metabolism
> Stimulates immune system
> Contributes to weight management
Weight management drugs :
–Enormous activity in Pharma, many targets
–Several compounds in the pipeline but no breakthroughs or miracles on the horizon yet
–From a medical point of view bariatric surgery is more effective for severe obesity
•Medicines to reduce complications of obesity are thus far more promising
•Pay attention to pharmacology aiming to increase food-intake (...another time..)
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Lecture 10 Pharmacology of inflammation
Inflammation in infection, injury and chronic disease
Atherosclerosis is caused by chronic inflammation.
Inflammation: a protective tissue response to injury or destruction of tissues, which serves to
destroy, dilute, or wall off both the injurious agent and the injured tissues.
 Heat, redness, swelling, pain, loss of function: Thus, a generic and functional response.
Acute inflammation: a rapid response to injury or microbes and other foreign substances designed to
deliver leukocytes and plasma proteins to sites of injury
Chronic inflammation: inflammation of prolonged duration in which active inflammation, tissue
injury and healing are occurring more or less simultaneously
Depending on the trigger, the inflammatory response has a different physiological purpose and
pathological consequences.
Of the three possible initiating stimuli, only infection induced inflammation is coupled with the
induction of an immune response.
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Anti-inflammatory drugs*
* NSAIDs (COX-inhibitors)
* LOX inhibitors
* Leukotriene receptor antagonists
* PG antagonists
* PAF inhibitors
* Corticosteroids
 most common, first choice
new developments
 not specific anti-inflammatory, like many others
NSAID GI toxicity
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The arachidonate metabolites are eicosanoids. The glucocorticoids inhibit transcription of the gene
for cyclo-oxygenase-2, induced in inflammatory cells by inflammatory mediators. The effects of
prostaglandin (PG) E2 depend on which of the three receptors for this prostanoid are activated.
HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; LT, leukotriene;
NSAID, non-steroidal anti-inflammatory drug; PAF, platelet-activating factor; PGI2, prostacyclin; TX,
thromboxane.
Gastric ulceration due to NSAIDS; therefore, commonly used in combination with proton pump
inhibitors
Corticosteroids: broad immuno-suppressants
• Derived from gluco-corticosteroids
• Used in many diseases
• Many (and complex-) interactions with immune-functions, including:
* inhibition of transcription of genes for COX-2, many cytokines, cell adhesion molecules, iNOS et.
* increased synthesis and release of anti-inflammatory cytokines, including annexin-1 (antiinflammatory feedback)
• Different molecules (potency, kinetics etc.) available
Taking corticosteroids  Cushing’s syndrome: Moon face with red cheeks, tendency to
hyperglycaemia + increased appetite + obesity: fat on the back (Buffalo hump), increased abdominal
fat, thinning of skin, osteoporosis: muscle wasting, negative nitrogen balance, increased
susceptibility of infection: easy bruising, prone to infection, poor wound healing.
Another mediator of inflammation: Nitric oxide
Sources and effects of nitric oxide (NO) in inflammation. NO synthesized by endothelial cells (mostly
via endothelial cell [type III] NO synthase [eNOS]) and by macrophages (mostly via inducible [type II]
NO synthase [iNOS]) causes vasodilation and reduces platelet and leukocyte adhesion; NO produced
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in phagocytes is also cytotoxic to microbes.
- Cytokines: polypeptides released during inflammation that regulate the action of inflammatory and
immune system cells.
- The cytokine superfamily includes the interferons, interleukins, tumour necrosis factor (TNF),
growth factors, chemokines and colony-stimulating factors.
- Interleukin (IL)-1 and TNF-α are important primary inflammatory cytokines inducing the formation
of other cytokines.
- Interferon (IFN)-α and IFN-β have antiviral activity, and IFN- is used as an adjunct in the treatment
of viral infections. IFN-beta has significant immunoregulatory function and is used in the treatment of
multiple sclerosis.
Infliximab (RemicadeR)
Anti-TNF MAb (chimeric type) = Monoclonal Antibody
Indications: rheumatoid arthritis, Crohn’s disease, colitis ulcerosa, arthritis psoriatica, psoriasis,
spondylitis ankylosans
Chronic inflammation
Diseases and conditions with a recognised inflammatory component (1):
Rheumatoid arthritis, Crohn's disease, Ulcerative colitis, Lupus, Type-1 diabetes, Type-2 diabetes, Cystic
fibrosis, Asthma, Allergic disease, Chronic obstructive pulmonary disease, Psoriasis, Multiple sclerosis,
Neurodegenerative disease of aging, Atherosclerosis, Acute cardiovascular events, Obesity, Response to
surgery, injury, trauma and critical illness, Acute respiratory distress syndrome, Cancer cachexia
Rheumatoid Arthritis
Auto-immune disease
- Pain
- Joint swelling: • Synovial thickening • Inflammatory cell infiltration
• Progressive destruction of cartilage and bone
- Morning stiffness
- Deformities
 Systemic chronic inflammatory disorder: Cachexia /Chronic fatigue / Depression
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Evolution of resolving versus
nonresolving inflammation at
a cellular level.
Inflammation in obesity
Adipose tissue is inflamed tissue
Inflammatory cells  Risks  Complications (-genetic predisposition – environmental/other
conditions)  Disease
Inflammation and insulin resistance are central to obesity-induced metabolic disease:
Lean and obese adipose tissues are associated with distinct (changed) macrophage phenotypes.
There are many (plant) compounds in your diet with an anti-inflammatory compound/action.
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Meta inflammation: chronically increased constant elevation of inflammatory status
N-3 fatty acids can modulate inflammation (2)
Omega 6
Omega 3
Omega 3
Omega 3 FA are substrates and they can give rise to other products (PGE3 instead of PGE2 (antiinflammatory prostaglandins)) following exactly the same pathways and they give rise to the
synthesis of resolvings.
Sickness behaviour
Lethergia, malaise, apathy, poor concentration etc.
Defense mechanism?
• saves energy
• stimulates restoration
• limits further exposure
Chronic activation of the innate immune system can cause depression = major risk factor
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Lecture 11 Drug discovery and development
Current challenges in development of new drugs:
> Increase of R&D costs
> Decline in productivity (low hanging fruit = picked)
> Cuts and limits by governments and health insurers
> Patent expiries, more competition
However...
> World-wide demand for (new) drugs still rising
> Many unmeant medical needs
> More aged persons with buying power and demand for adequate medical care
Development is where the money is…
Rising costs.
After 1996 decline in new drugs.
Some drugs fail.
‘Drugs don’t work (more than 90% works only in 30-50% of people) in particular in complex diseases.
Pharma R&D model
Basics of the current R&D process
- Pipeline model
- Continuous selection and attrition process
- Validated drug targets are essential
- So are the compound “libraries”
rubbish in, rubbish out
- Alternative pathways are increasing (for example by buying in)
Principles of early drug discovery
HTS: high throughput screening
57
Drug discovery
58
Disease models:
* Disease progression
* Pathway elucidation
* Animal model validation
* Target discovery
* Target validation
* Safety/ Efficacy
* Mechanism of action
* Diagnostics/ (bio) markers
59