PHRM20001 - Drugs & MoA

Noradrenaline

A neurotransmitter and hormone that plays a key role in the body's stress response, known for increasing heart rate and blood flow.

Adrenaline

A hormone and neurotransmitter that helps mediate the body's fight-or-flight response, primarily increasing heart rate, blood flow, and energy availability.

Catecholamine synthesis in Nerve Terminals

• L-tyrosine transported into nerve terminal by L-tyrosine transporter

• L-tyrosine hydroxylated by tyrosine hydroxylase into L-DOPA

• L-DOPA is decarboxylated by DOPA decarboxylase into Dopamine

• Dopamine is transported into the synaptic vesicles by Vesicular monoamine transporter (VMAT)

• Dopamine β-hydroxylase converts dopamine into Noradrenaline

Catecholamine synthesis in chromaffin cells

• L-tyrosine hydroxylated by tyrosine hydroxylase into L-DOPA

• L-DOPA is decarboxylated by DOPA decarboxylase into Dopamine

• Dopamine is transported into the chromaffin granules by Vesicular monoamine transporter (VMAT)

• Dopamine β-hydroxylase converts dopamine into Noradrenaline

• PNMT converts noradrenaline into Adrenaline

Reserpine

VMAT inhibitor that inhibits transport of neurotransmitters into the synaptic vesicles, therfore stopping the synthesis & release of Noradrenaline.

NOT used therapeutically

Drugs targeting neurotransmitter reuptake

Cocaine, TCAs

Drugs targeting neurotransmitter metabolism

MAO inhibitors

Tyramine

Dietary product that doubles as a MAO substrate. Patients taking IASs should avoid foods with the product (e.g. Vegemite, cheese, cured meat)

Ephedrine

Mixed-acting sympathomimetic used for post-operative hypotension

Acetylcholine

The primary neurotransmitter of the parasympathetic nervous system (PNS) and the somatic nervous system (SNS).

Atropine

Competitive reversible muscarinic receptor

What is atropine used for

To reduce secretions during anaesthesia & treat anticholinesterase poisoning

d-Tubocurarine

Competitive reversible nicotinic receptor antagonist (at neuromuscular junctions)

What is d-Tubocurarine used for?

In surgical paralysis as a neuromuscular-blocking drug

d-Tubocurarine adverse effects

• Hypotension

  • due to ganglion-block

• Replaced with drugs that are less effective at autonomic ganglia

Gefitinib 

EFGR inhibitor used to treat lung cancer. EFGR mutations can predict success of this drug/impacts its efficacy

Warfarin

VKORC1 antagonist that reduces coagulative factors

Polymorphisms affecting warfarin effectiveness

• cytochrome c450 

  • at 2C9 (CYP2C9)

  • reduces wafarin concentration

• VKORC1

  • affects affinity

Terfenadine

Histamine H1 receptor antagonist used toi treat seasonal allergic rhintitis

Terfenadine mechanism of action

• almost 0% bioavailability

  • prodrug

• converted into fexodenadine

  • converted by p450 enzyme CYP-34A

Grapefruit juice

Contains dihydroxybergammotin - a CYP-34A inhibitor

Terfenadine + grapefruit juice interactions

Causes life-threatening ventricular dysrhythmia.

• Terfenadine becomes bioavailable & inhibits K+ channels

Salicylate

Active constituent in willow & spirea with properties of NSAIDs (were made synthetically to match the response of this natural compound)

Coxibs

selective COX-2 inhibitors

Rofecoxib/Vioxx

• selective COX-2 inhibitor

• withdrawn due to increased risk of cardiovascular death

Therapeutic Antibodies Mechanism of Action

• Chemical antagonism

  • ligand

  • receptor

  • receptor dimerisation

  • induces apoptotic signalling

• Recruit immune cells to mediate killing

  • mechanism for cancer treatment

Adalimumab

• Fully human antibody

• Chemical antagonist

• Binds to Tumour Necrosis Factor (TNFα)

  • used to treat rheumatoid arthritis 

Tocilizumab

• Humanised (?) antibody

• Receptor antagonist 

• Binds to IL-6 receptor 

  • used to treat inflammatory disorders

    • e.g. rheumatoid arthritis

Dupilumab

• Fully human antibody

• Receptor antagonist

• Binds to IL-4 & IL-13 receptors

  • used to treat asthma

Mepolizumab

• Humanised antibody

• Chemical antagonist

• Binds to IL-5

  • used to treat asthma

Edrophonium 

Short-acting ACh antagonist

Phenylephrine

alpha 1-adrenoreceptor agonist 

Apraclonidine 

Selective alpha 2-adrenoreceptor antagonist. Weak agonist at alpha 1, thus causing upregulation of those receptors

Salbutamol

Beta2-adrenoceptor agonist. Antagonises the effects of endogenous contractile agonist that act at different receptors. Used to treat acute asthmatic attack.

Neostigmine 

Reversible cholinesterase inhibitor selective for neuromuscular junctions. Used to treat Myasthenia Gravis.

Botulinum toxin A

ACh release antagonist, used both cosmetically & clinically.

Physostigmine

Reversible cholinesterase inhibitor selective for parasympathetic junctions. Used to treat glaucoma. 

Atropine

Competitive reversible muscarinic antagonist used to reduce secretions during anaesthesia & treat anticholinesterase poisoning. 

Short-acting beta2-adrenoceptor agonists (SABA)

• e.g. Salbutamol, Terbutaline

• activates adenylate cyclase

  • increases cAMP → activates protein kinase A → decreases cytoplasmic Ca2+ → inhibits contractile process

• acute symptom relief 

• must be used with an inhaled corticosteroid

• 2-5 minute onset & 2-4 hour duration

Long-Acting beta2-adrenoceptor agonists (LABA)

• e.g. salmeterol (slow onset), formoterol (rapid onset)

• activates adenylate cyclase

  • increases cAMP → activates protein kinase A → decreases cytoplasmic Ca2+ → inhibits contractile process

• Long-lasting airway relaxation

Glucocorticoids MoA

Alter protein synthesis - increase expression of anti-inflammatory genes (annexin-1, beta2-adrenoceptors), decreases expression of inflammatory genes (COX-2, PLA2, TNF-alpha, ICAM-1)

Cysteinyl-leukotriene receptor antagonist

Has both anti-inflammatory & broncho-relaxant effects

Beta2-adrenoceptor agonist adverse effects

Tremors, tachycardia & palpitation, headaches

Glucocorticoid adverse effects (Inhalation)

Hoarseness & weakness of voice (potential atrophy), oral thrush

Glucocorticoid adverse effects (Oral)

Suppression of HPA axis, mood changes, weight gain, hyperglycaemia, osteoporosis, hypertension, immune suppression

Beta-adrenoceptor antagonists

• Decrease HR → decreases contractability → decreases CO → decreased BP

  • inhibits beta1-adrenoceptors by noradrenaline & circulating adrenaline

• decreases blood volume

  • Inhibits kidney beta1-adrenoceptors

Beta-adrenoceptor antagonists adverse effects

• decreased exercise capacity

• muscle fatigue

• cold extremities

• bronchoconstriction

• dreams & insomnia

Prazosin

alpha-adrenoceptor antagonist involved in inhibiting sympathetic activation of blood vessels to lower TPR

Prazosin MoA

• Binds to & inhibits vascular alpha1-adrenoceptors

• inhibits noradrenaline-mediated vasoconstriction

• Decreases TPR

  • Decreases BP

Prazosin Side effects

1st dose hypotension, nasal congestion, postural hypotension, initial reflex tachycardia

RAAS Inhibitors MoA

• ACE inhibitor

  • prevents production of angiotensin II

  • inhibits bradykinin breakdown

• AT1R antagonist

  • prevents endogenous angiotensin II from binding to AT1R

  • Lowers Na+ & water retention

RAAS inhibitors adverse effects

1st dose hypotension, hyperkalaemia, acute renal failure, dry cough

Advantages of RAAS inhibitors

• Less effect on cardiovascular reflexes

• Safe in asthmatics

• Beneficial effects on cardiovascular remodelling

Calcium channel antagonists MoA

• Inhibits L-type VOCC

• Decreases Ca2+ entry in vascular smooth muscle

• Decreases vascular contractile tone

• decreases TPR due to arteriolar dilatation

  • decreases BP

Calcium channel antagonists adverse effects

• initial reflex tachycardia

• flushing

• headaches

Biguanides MoA

• reduce hepatic glucose production

  • activation of AMP-activated protein kinase in liver inhibits gluconeogenesis

• increases insulin-mediated glucose uptake

• decreases carbohydrate absorption

• reduces LDL cholesterol & triglyceride levels

Biguanides Adverse effects

• GI disturbances

• Lactic acidosis if improperly prescribed

• no weight gain with possible modest weigh loss

• Contraindicated in patients with renal & hepatic disease

Sulfonylureas MoA

• Acts on beta-cells to stimulate insulin secretion

• Binds to K_ATP channel

Sulfonylureas Adverse effects

• Hypoglycaemia

• Weight gain

SGLT2 inhibitor MoA

Prevents glucose reabsorption

SGLT2 inhibitor adverse effects

• Genital infections

  • UTI

  • thrush

• Polyuria

• Thirst

• Modest weight loss

Alpha-glucosidase inhibitors MoA

• Alpha-glucosidase antagonist - enzyme in small intestine that digests & promotes CHO

• delays carbohydrate absorption

• Decreases postprandial rise in glucose

Alpha-glucosidase inhibitor adverse effects

Flatulence, abdominal discomfort, loose stools, contraindicated in patients with IBS

Exogenous insulin adverse effects

Hypoglycaemia (faintness, sweating, tremor), allergic reaction and lipodystrophy (rare), drug interactions (beta-blockers, corticosteroids, diuretics, alcohol)

Phentermine

Indirectly-acting sympathomimetic that increases NA available to bind to receptor, supressing appetite

Phentermine adverse effects

Tachycardia, insomnia, agitation, dry mouth

Orlistat MoA

Inhibits gastric & pancreatic lipases → decreases dietary fat absorption

Orlistat Adverse effects

Mainly GI & controlled if patients adhere to a low-fat diet, explosive diarrhoea & faecal fat leakage (may lead to poor compliance). Vitamin supplementation is therefore recommended  

GLP-1 agonist actions

• Pancreas - binds to beta cells → stimulates insulin production & secretion, binds to alpha cells → inhibits the release of glucagon

• Liver - inhibits gluconeogenesis

• Muscle & fat tissue - increases insulin-mediated glucose uptake

• Stomach - delays gastric emptying

• Intestines - delays release of food into intestine, lows pre-prandial peak in glucose

• Brain - inhibits appetite in hypothalamus

GLP-1 agonist adverse effects

Nausea, vomiting, diarrhoea, injection site reactions, pancreatitis 

Methaqualone (Lemmon Quaalude) MoA

Positive allosteric modulator for GABA_A receptor subtypes. CNS depressant that actions as a sedative & hypnotic drug

Benzodiazepines 

positive allosteric modulator of fast inhibitory transmission by GABA at GABA_A receptors

Dopamine agonists

Used to improve bradykinesia & rigidity caused by neurodegenerative disorders

MAO_B inhibitors

Used in the treatment of neurodegenerative disorders to reduce dopamine metabolism & formation of ROS

Tricyclic antidepressants MoA

• block re-uptake of NA, 5HT into nerve terminal

• Inhibits serotonin, norepinephrine, & dopamine transporters

• allows for downregulation of post-synaptic receptors

Tricyclic antidepressants adverse effects

Sedation, anti-ACh, lower BP, increased weight, cardiac effects, seizures (infrequent), risk of OD

MAO inhibitors MoA

• Increased monoamine concentration in cytoplasm 

  • long-lasting inhibition

• antidepressant effect related to beta-receptor & 5HT receptor downregulation 

  • delayed effect

• Increases NA, 5HT, DA in presynaptic terminals

Selective serotonin uptake inhibitors (SSRIs) MoA

• Selective for 5HT uptake

• Weak inhibition of NA, DA uptake

• Few adrenergic, histamine, muscarinic effects

• Actual MoA unknown

• Ser-438 residue in hSERT determining factor in SSRI potency

SSRI Adverse Effects

nausea, insomnia, agitation, weight change, loss of libido. 

Mirtazapine

3rd gen antidepressant that inhibits alpha2-adrenoceptors & 5-HT receptors

Ketamine as depression treatment

• reduces depressive symptoms for people who are treatment-resistant

• reduces suicidal  thought/ideation

• NMDA receptor antagonist

  • non-competitive

Cocaine MoA