Clinical Pharmacology PDF

– Orthostatic hypotension due with liver disease. These drugs are to their α-receptor blocking now withdrawn from the market. action. Interactions These drugs can potentiate the Dangerous arrhythmia when sedative effe...

– Orthostatic hypotension due with liver disease. These drugs are to their α-receptor blocking now withdrawn from the market. action. Interactions These drugs can potentiate the Dangerous arrhythmia when sedative effect of hypnotics, given with other drugs that inhibit alcohol, etc. CYP450 system. █ Serotonin (5-hydroxytryptamine; 5-HT) 5-HT is formed from the amino acid tryptophane and stored mainly in the enterochromaffin tissue of the GIT (90%) and platelets (10%). Serotonin is found also as a transmitter in many areas within the CNS. Like histamine, no clinically useful drugs affect the synthesis or metabolism of 5-HT, but many drugs can act on 5-HT receptors as agonists or antagonists. Pharmacological actions of 5-HT 5-HT acts on at least 7 types of receptors: Distribution Postreceptor Effect mechanism 5-HT1A CNS, cranial Gi Role in anxiety, cognitive function, 5-HT1B blood vessels ↓cAMP appetite, thermoregulation, memory, 5-HT1D nociception 5-HT1E VC of cranial BV. 5-HT2A Platelets Gq Platelet aggregation (5HT2A) 5-HT2B smooth muscle, ↑ IP3 VC and smooth muscle contraction 5-HT2C CNS Hallucinations 5-HT3 Area postrema, Na+ ion Nausea and vomiting enteric nervous channel Nociception (pain) system 5-HT4 CNS and enteric Gs ↑ GIT motility and secretions nervous system ↑ cAMP 5-HT5A CNS Gi ? ↓cAMP 5-HT6,7 CNS Gs Anxiety, cognitive function, ↑ cAMP thermoregulation, memory, nociception 115  █ Som me 5-HT agonists s and an tagonistts in clinical use ▌5-HT T agonists s Bus spirone: (ssee also CN NS) – It acctivates ceentral 5-HT T1A recepttors. It is used forr treatment of an nxiety diso orders esppecially in elderly e patiients. – Theerapeutic effect e may take as lo ong as 2wweeks to apppear. Trip ptans: sumatriptan n, zolmitrriptan, narratriptan (ssee also AN NS) – Theey activate 5-HT1B/1D receptors.. – Thee major usse of tripta ans is the treat- men nt of acutte migrainne. Activat ion of 5-HHT1D recepptors inhibiits inflammmation of meninges,, pain transmission , and rele ease of VD D substannces e.g. calci- toniin gene-related peptide in trigeeminal neuurons. Activation of 5-HT 5 1B rec ceptors ca auses VC of o the dilaated cerebral ves- selss. About 500%–80% of o patients report reliief from pa ain within 2 hours. – 5-HHT1B activitty can cause corona ary spasmm so; these e drugs arre contraindicated in p patients witth ischemic c heart dissease (IHD). Teg gaserod: – It iss a specificc 5-HT4 ag gonist. It in ncreases GIT G motility y so it is uused for tre eatment of irrritable bow wel syndro ome with c constipation. ▌5-HT T antagon nists Cyp proheptad dine: – It bllocks 5-HTT2, H1, & muscarinic m c receptors s. – It is used for treatment t of o symptomms of carc cinoid tumo or and as aantiallergic c. Aty ypical antip psychotics: Olanzap eridone (see also CN pine, rispe NS) – Theey block 5-HT2A and a dopam mine D2 receptors in the CNS lead ding to imp provement of the neg gative symp ptoms of schizophre s enia. Ond n, granisettron: (see a dansetron also GIT) – Theey selectiveely block 5-HT 5 3 recep pherally (GIT). ptors centrally (CTZ) and perip – It is used for trreatment off nausea & vomiting asssociated with w cancerr chemothe erapy. 116 █ Kiniins (brad dykinin)  Kiniins are potent p va asodilator peptides form med from m protein substrate es called kininogen byy the effect e of kallikrein enzyme.  Kiniins act on o at lea ast 2 sub btypes of rece eptors: B1 1 and B2 2. Activatio on of B2 rece eptors ca auses VD D and ↑ capillary permmeability, smooth ms co ontraction (bro onchoconsstriction, GIT G colic, etc.), and stim mulation of sensory nerves n caussing pain.  Icattibant is a 2nd gene eration dec capeptide which acts as a a selecctive anta agonist at braddykinin B22 receptorrs. It is give en by s.c. injection for the t symptoomatic tre atment of acuute attackss of hereditary angioedema. It mmay also be usefu ul in drug g-induced anggioedema, ascites, annd pancrea atitis.  Reccently, a 3rd generation of oraally active B2--receptor antagonists was d developed and d currently under stud dy. █ End dothelins s  End dothelin is a vasocon nstricting p peptide pro oduced by the endotthelium. Th here are 3 issoforms. Endotheliin-1 (ET-1 1) is one of the strongest vasocons strictors currrently stud died.  End dothelins act a on at least 2 subtyypes of rec ceptors: ET TA and ET TB.  Mosst of ET-1 effects are a mediatted throug gh ETA rec ceptors pre resent in vascular v smo ooth ms an nd other tissues. Its activation leads to potent p VC,, vascular smooth ms proliferatio on, cardiac c hypertropphy, and elevation e off blood preessure.  Incrreased pro plicated in a variety of CVS diseases, oduction of ET-1 hass been imp including prim mary pulmmonary hyp pertension phy, heart failure, n, cardiac hypertrop athe erosclerosis, and corronary arte ery disease e.  Bossentan is orally activve nonseleective bloc cker of ET TA and ETBB receptors s, while ambrisentan is a selec ctive ETA b blocker. Bo oth drugs are approv oved for tre eatment of p pulmonary y hypertennsion. 117  █ Purines as mediator m rs Nucleoosides (adeenosine) an nd nucleottides (ADPP and ATP P) are extraacellular chemical mediators. ATP isi stored in vesicless and relea ased by ex xocytosis or through h tissue damage. Released ATP is s rapidly converted to ADP and adennosine. The three puriness act on th hree main families oof purine receptors r and exertt a wide ra ange of functions. ▌Drug gs acting on purine recepto ors: Adeno osine It is a sshort actin ng purine A recepto r agonist. It is given n by i.v. ro oute to inh hibit AV conduc ction and converts c supraventr s chycardia to the sinuus rhythm in non- ricular tac asthma atic patientts (see CVS S). Methy ylxanthine es Caffein ne, aminop phylline and d theophyylline are purine p A1 receptor r antagonistts. They a are use ed as bron nchodilatoors and CN NS stimula ants (see re espiratory)). 118