Pharmacology of Inflammation Lecture 1 PDF

PHARMACOLOGY OF INFLAMMATION Newman Osafo, BPharm, PhD Department of Pharmacology, FPPS, CoHS, KNUST [email protected]  INFLAMMATION  Inflammation is a local reaction to injury or invasion associated with swelling and pain.  The inflammatory response alth...

PHARMACOLOGY OF INFLAMMATION Newman Osafo, BPharm, PhD Department of Pharmacology, FPPS, CoHS, KNUST [email protected]  INFLAMMATION  Inflammation is a local reaction to injury or invasion associated with swelling and pain.  The inflammatory response although primarily defensive often results in tissue damage serious enough to warrant pharmacological intervention 2 TISSUE RESPONSE TO INJURY 3 Divided into three (3) phases  Acute Phase  Initial response to tissue injury  Release of autocoids  Immune Response  Immunologically competent cells are activated in response to antigenic substances  Chronic Inflammation  Release of numerous cellular mediators 4 INTRODUCTION  Autacoid: Greek autos (self) akos (medical agent, remedy).  Autacoids have a brief duration, act near site of synthesis, and are not blood borne. They are "Local hormones". 5 INTRODUCTION  Autacoids are a heterogeneous group of pharmacologically active compounds which are formed by the tissues they act on  thus they function as local hormones.  Autacoids include histamine, serotonin, AA Metabolites, PAF 6 INTRODUCTION  Autocoids are substances that are called into play in the defense of the body.  Theirimportance lies mainly in their roles in inflammation and allergic responses. 7 HISTAMINE  Chemical mediator of a wide variety of cellular responses including allergic and inflammatory reactions, and gastric acid secretion. 8  Biosynthesis L-histidine decarboxylase L-histidine Histamine  Histamine is synthesized in mammalian tissues by decarboxylation of the amino acid L-histidine.  The reaction is catalyzed by histidine decarboxylase 9 TISSUE LOCALIZATION (STORAGE):  The chief site of histamine storage in most tissues is the mast cell.  In the blood, the major site of storage is in the basophil. 10  Histamine is stored in bound form in granules along with  heparin,  eosinophil chemotactic factor of anaphylaxis (ECF-A),  neutrophil chemotactic factor  and various enzymes such as (-glucuronidase, neutral proteases, superoxide dismutase and peroxidase.  The bound form of histamine is biologically inactive 11  1. RELEASE WITHOUT MAST CELL INJURY OR DEGRANULATION  Certainchemicals such as morphine, succinylcholine, d- tubocurarine have the capacity to release histamine.  These substances displace histamine from the heparin-protein complex within mast cells.  Because of this property, the narcotic analgesics may cause intense itching when used in the treatment of pain.  Some addicts also complain of itching.  Intravenous injection of organic bases, i.e., quaternary amines, antibiotic bases, alkaloids, etc. can also release pharmacological amounts of histamine. 12 2. RELEASE WITH MAST CELL INJURY  Loss of storage granules from the mast cell into the extracellular fluid results in rapid release of histamine.  Sodium ions in the extracellular fluid rapidly displace histamine from its binding complex with polysaccharide, heparin and protein.  The redness and urticaria that follow scratching of the skin exemplifies histamine release due to nonspecific cell damage. 13 3. IMMUNOLOGIC RELEASE (DEGRANULATION). i) Interaction of antigen with macrophage to produce an antibody (e.g., IgE). ii) Interaction of IgE antibody and antigen (allergen) with mast cell to release histamine. 14 MAST CELL 15 RELEASE (SUMMARY) 1. Pharmacologic (direct release)  Morphine  Tubocurarine  Succinylcholine  Radiocontrast media  Carbohydrate plasma expanders  Vancomycin (red-man syndrome) 2. Physical stimuli – scratching the skin 3. Immunologic - usually a component of an immediate hypersensitivity reaction (IgE) 16  REGULATION OF RELEASE  Mast cells and basophils contain receptors linked to signaling systems that can enhance or block the IgE- induced release of mediators.  Inhibition of release is produced by adrenaline and other drugs that activate (β-receptors).  Stimulation of these receptors results in the accumulation of cAMP which is responsible for reducing histamine release.  Histamine reduces its own release by interacting with H2 receptors on mast cells and basophils. 17 RELEASE INHIBITORS  Adrenaline  Theophylline Inhibits PDE thereby causing increase in cAMP  Isoproterenol  Mechanism: β-adrenoceptor activation and cAMP accumulation 18  RELEASE OF OTHER AUTACOIDS WITH HISTAMINE.  A multiplicity of released chemicals accounts for the allergic response.  Alone, the histamine hypothesis of immediate hypersensitivity reactions is INCOMPLETE.  The release of histamine provides only a partial explanation for the spectrum of effects which characterizes immediate hypersensitivity reactions.  The mast cell secretes many inflammatory compounds in addition to histamine. 19  Each contributes to the major symptoms of the allergic response:  constriction of bronchi,  decrease in blood pressure,  increased capillary permeability and edema.  Also, the many mediators released during the allergic response accounts for the ineffectiveness of drug therapy focused on a single mediator. 20  Other mediators released in the allergic response include:  PAF  leukotriene D4. induce the contraction of smooth muscle, resulting in bronchoconstriction and vasoconstriction. It also increases vascular permeability.  This latter compound, LD4, causes contraction of bronchial smooth muscle and may be a dominant influence in allergic conditions such as asthma 21  HISTAMINE RECEPTORS:  Acts by binding to four types of receptors, H1, H2, H3, and H4  Histamine stimulates all four  Certain drugs selectively stimulate and block these receptors 22  H1 elicits ↑ in IP3 and DAG classical antagonist is pyrilamine, cyclizine  H2 mediated through ↑ in cAMP classical antagonist is cimetidine, ranitidine  H3 – ↓ cAMP. Autoreceptor that also decreases ACh, NE, Serotonin release classical antagonist is thioperamide  H4 – ↓ cAMP. Mediates mast cell chemotaxis classical antagonist (nonspecific) is thioperamide, pimozide 23  ANATOMICAL LOCATION OF RECEPTORS  H1 receptors are located on the smooth muscles of the intestine, bronchi, trachea, capillaries and CNS  H2 receptors are located on uterine smooth muscle, cardiac muscle, gastric glands and CNS  H3 receptors are predominantly located within the brain particularly the cerebral cortex.  H4 receptors are part of the immune system.  On vascular smooth muscle that is responsible for vasodilator responses, both H1 and H2 receptors are present. 24 METABOLISM - BIOLOGICAL INACTIVATION, DEGRADATION AND EXCRETION.  Histamine is inactivated by enzymatic metabolism and by transport processes that reduce the concentrations of this substance in the vicinity of its receptors.  The metabolites of histamine have little or no histamine-like effects in mammalian tissues.  They are excreted in the urine. 25  Metabolism  The two major pathways of degradation are catalyzed by the enzymes:  Histamine-N-methyltransferase. This enzyme converts histamine to 1- methylhistamine-methylation Brain & periphery Periphery  Diamine oxidase “DAO” (histaminase). This enzyme converts histamine to imidazole acetic acid – oxidative deamination 26 PHYSIOLOGICAL ROLES OF HISTAMINE  Hypersensitivity and allergic responses  Histamine release is partially responsible for allergic responses.  Regulation of gastric acid secretion.  Histamine evokes a copious secretion of acid from parietal cells by activating H2 receptors. Other physiological factors also play some role in gastric acid secretion.  Blockade of H2 receptors blocks acid secretion in response to histamine and causes essentially complete inhibition of responses to other releasing agents such as gastrin or vagal stimulation. 27  Neurotransmitters in the CNS.  Histamine appears to function as a transmitter in the CNS.  High concentrations of H1 receptors occur in the thalamus, hypothalamus, and regions of the cerebellum.  Histaminergic neurons may play a role in the regulation of drinking, body temperature regulation and secretion of antidiuretic hormone, the control of blood pressure and the perception of pain.  Both H1 and H2 receptors appear to play a role in these responses.  H3 receptors are apparently located on histaminergic nerve terminals, where they exert feedback regulation of histamine synthesis and release. 28 C.V.S.  Vascular smooth vessels  Vasodilation: H1& H2  Flushing  ↓ peripheral resistance  ↓ blood pressure  ↑ capillary permeability: H1 29 INCREASED VASCULAR PERMEABILITY  H1 receptor activation produces inhibitory effect of histamine on the post capillary venules.  This causes endothelial cells to contract and become separate at their boundaries thus exposing the basement membrane which is freely permeable to plasma proteins and fluid.  The overall increased permeability results  in outward movement of plasma protein and fluid into the extracellular spaces,  an increase in the flow of lymph and in its protein content, the formation of oedema.  The involvement of H2 receptors in this effect is not certain. 30  THE HEART  +Ionotropic effect both atria and ventricular resulting from the promotion of calcium flux. This effect is predominantly H2 activity.  +Chronotropic effect by increasing diastolic depolarization in the S.A. Node (predominantly H2 activity).  Slowing down of A.V. conduction (-dromotropy) to increase sinus rate and ventricular automaticity of the heart (predominantly H1 activity).  In high doses histamine causes diverse arrhythmia (H2 activity). 31 VASODILATION  Histamine- induced vasodilation is mediated via both H1 and H2 receptors present in most vascular smooth vessels.  H1 receptors are the most sensitive because of their higher affinity for histamine.   H1 receptor induced dilation is rapid in onset and of short duration,  The vasodilation results primarily through H1 receptor mediated release of EDRF (nitric oxide). – H2 receptor induced dilation is slow in onset and more sustained. 32 SYSTEMIC BLOOD PRESSURE  Moderate doses of histamine cause a fall in systemic blood pressure.  This fall is due to a reduction in peripheral resistance and dilatation of the peripheral blood vessels.  There are 2 components of this response;  H1 receptor mediated; this is rapid in onset but transient  H2 receptor mediated; this is slower in onset but sustained  The fall in systemic BP triggers baroreceptor reflexes which call into play increased sympathetic discharge leading to a reversal of the fall of the BP – a biphasic BP effect 33  High doses of histamine will produce histamine shock. There is a profound and sustained fall in the BP. The body itself cannot compensate for it Leading to no reversal.  This fall in BP is due to;  dilation of minute blood vessels  pooling of blood in the peripheral vascular bed  increased vascular permeability therefore loss of plasma fluid and proteins from the circulation  drastic fall in blood volume  reduction in venous return and a fall in the cardiac output  collapse of large arteries  Histamine shock is mainly due to the injection of exogenous histamine.  Endogenous histamine can be mobilized in the body by taking drugs which release histamine and the state of such a person may resemble that of one due to exogenous histamine. 34  EXTRAVASCULAR SMOOTH MUSCLES:  Histamine causes contraction of the smooth muscle (H1 receptor activation).  There is also relaxation (H2 receptor activation).  The tissue responses relating to smooth muscles are species dependent. For example,  Human bronchial smooth muscle is normally not very sensitive but in subjects predisposed to bronchial asthma and some other pulmonary diseases, there can be intense bronchospasms to minute doses of histamine. 35  SENSORY NERVE ENDINGS  Introduction of histamine into the superficial layers of the skin produces itching.  When administration is made more deeply into the skin then pain is produced. "Triple Response (of Lewis)": (red, intense flare, wheal) 36 PHYSIOLOGICAL FUNCTIONS OF ENDOGENOUS HISTAMINE  Hypersensitivity & allergic responses (one of the mediators in local and systemic allergic reactions) SRS-A, ECF-A ???  Mediator of gastric acid secretion  Neurotransmitter in the CNS 37 ADVERSE EFFECTS & CONTRAINDICATION  Flushing  Hypotension,  Tachycardia,  Headache,  Wheals,  Bronchoconstriction,  Gastrointestinal Upset.  Histamine is contraindicated in asthmatics and patients with active ulcer disease or GI bleeding. 38 ANTIHISTAMINES  H1 blockers  H2 blockers 39 H1 BLOCKERS  1st generation antihistamines are more likely to  cause sedation in therapeutic doses  affect autonomic receptors (cholinergic and adrenergic)  2nd generation antihistamines are sometimes called “non-sedating” antihistamines 40 1ST GENERATION  Developed in France pre-WWII  More sedating  Penetrate the CNS and generally have CNS effects  Significant anticholinergic effects 41 2ND GENERATION  Less sedating - less CNS penetration  Almost no anticholinergic effects  Some can produce cardiac toxicity e.g., terfenadine, astemizole and ebastine. 42 2ND GENERATION ANTIHISTAMINES  Ionized molecules that cross BBB poorly.  Loratidine (Claritin™) – No apparent cardiac toxicity  Fexofenadine (Allegra™) - active metabolite of terfenadine, safer than parent compound  Rupatadine – anatgonist of PAF  Cetirizine (Zyrtec™) - metabolite of hydroxyzine  Removed from the market for serious cardiac arrhythmias  Terfenadine (Seldane™)  Astemizole (Hismanal™) 43 MECHANISM OF ANTIHISTAMINIC H1 ACTION  Competitive or surmountable antagonism contributes to most of the effects of H1 antagonists  But most of these drugs produce some of their effects through OTHER mechanisms.  Many of the H1 antagonists are also inhibitors of muscarinic receptors.  These atropine-like properties are sufficiently prominent with some of these drugs to be clinically significant. 44 HISTAMINE H1 RECEPTOR ANTAGONISTS Classification Generic name Trade Name(™) Ethanolamines Dimenhydrinate Dramamine Diphenhydramine Benadryl Carbinoxamine Clistin Ethylenediamine Pyrilamine Tripelennamine Alkylamines Chlorpheniramine Piriton Brompheniramine Dimetane 45 Piperazines Meclizine Antivert Cyclizine Marezine Phenothiazines Promethazine Phenergan/Avomine Miscellaneous Cyproheptadine Periactin 46 Bilastine and Acrivastine  Cause less sedation and psychomotor impairment  Limited information on its safety in pregnancy but no data on its teratogenicity  Bilastine has similar efficacy as cetirizine but significantly reduced somnolence (PMID: 22185046). 47 EFFECTS ON AUTONOMIC RECEPTORS ANTICHOLINERGIC ACTIONS  Anti-motion sickness effects/anti-emetics  Mechanism: Blocking of muscarinic receptors  Promethazine strongest muscarinic receptor blocking activity of clinically useful H1 antagonists  Others: Cinnarizine 48 LOCAL ANAESTHETIC EFFECTS  Promethazine & mepyramine particularly active  Less potent than dibucaine  Comparable to procaine  Tripelennamine & chlorpheniramine - cocaine-like action  Large doses higher than antihistamine doses required 49 CNS 1st generation antihistamines cross BBB and produce CNS depressant effect  Sedation  Cough suppression 50  PHARMACOKINETICS  Most well absorbed and remain effective for 3-6 h  Loratadine is converted to a long acting metabolite  Metabolism by the liver and excretion in the urine.  Most have peripheral antimuscarinic activity  Terfenadine is a prodrug requiring oxidation by CYP3A4 to to its safer metabolite (fexofenadine). The parent drug’s cardiotoxicity resulted in its withdrawal from the market. 51 SIDE EFFECTS  CNS – sedation, headache, visual disturbances dizziness, euphoria, tinnitus, insomnia, tremors  GIT  anorexia, epigastric distress, constipation,  ANTIMUSCARINIC EFFECTS -dryness of mouth & respiratory passages, urinary retention, etc 52  SIDE EFFECTS  DRUG ALLERGY Dermatitis, Urticaria, Rash  HAEMATOLOGICAL COMPLICATIONS Hemolytic anaemia, leukopenia  TERATOGENIC EFFECTS in experimental animals with piperazine derivatives like cetirizine 53 ACUTE POISONING  Central depression  Central excitation  Hallucinations  Convulsions  Coma  Cardio-respiratory collapse  Death 54 THERAPEUTIC USES  Allergy (hives, rhinitis, hay fever, conjunctivitis).  Bronchial Asthma  Common cold  Vertigo Vertigo is a feeling of spinning or tilting that can be caused by inner ear problems, brain problems, or medications  Nausea & vomiting  Parkinson’s disease (orphenadrine, diphenhydramine)  Insomnia  Prevention of Motion sickness & Emesis. 55